rs180177132

Positions:

• chr16-23621362-C-T

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM5_Supporting PVS1 PS4

This summary comes from the ClinGen Evidence Repository: The c.3113G>A (p.Trp1038Ter) variant in PALB2 occurs at the last nucleotide of exon 10. It is predicted to cause skipping of biologically-relevant exon 10, as well as partial deletion of exon 10, resulting in a frameshift leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism. This prediction is confirmed by RT-PCR analysis (PMID:21285249, 23448497). This alteration results in a termination codon upstream of the most C-terminus pathogenic alteration (PALB2 p.Tyr1183*), as classified by the HBOP VCEP, and is expected to be more deleterious. This variant is non-functional in multiple different protein assays (PMID 31757951); however due to a lack of positive missense controls with known clinical impact, these protein assays do not meet the requirements for use by the HBOP VCEP. The prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls [OR=4.21, 95% CI:1.84 - 9.60] (PMID:27595995). The highest population filtering allele frequency in gnomAD v2.1.1 is 0.00006665 in the European (Non-Finnish) population (PM2_Supporting, BS1, and BA1 are not met). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant hereditary breast and pancreatic cancer and autosomal recessive FANCN based on the ACMG/AMP criteria applied, as specified by the HBOP VCEP. (PVS1(RNA), PS4, PM5_Supporting). LINK:https://erepo.genome.network/evrepo/ui/classification/CA251004/MONDO:0016419/020

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00023 (0 hom.)
• Consequence: PALB2 ENST00000261584.9 stop_gained, splice_region
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic reviewed by expert panel P:31 O:2
• Conservation: PhyloP100: 4.74

Genes affected

PALB2 (HGNC:26144): (partner and localizer of BRCA2) This gene encodes a protein that may function in tumor suppression. This protein binds to and colocalizes with the breast cancer 2 early onset protein (BRCA2) in nuclear foci and likely permits the stable intranuclear localization and accumulation of BRCA2. [provided by RefSeq, Jul 2008]

(HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 13 ACMG points.

• PVS1: For more information check the summary or visit ClinGen Evidence Repository.
• PS4: For more information check the summary or visit ClinGen Evidence Repository.
• PM5: For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PALB2	NM_024675.4	c.3113G>A	p.Trp1038Ter	stop_gained, splice_region_variant	10/13	ENST00000261584.9	NP_078951.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PALB2	ENST00000261584.9	c.3113G>A	p.Trp1038Ter	stop_gained, splice_region_variant	10/13	1	NM_024675.4	ENSP00000261584	P1
	ENST00000561764.1	n.420-2538C>T		intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152144 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000597 AC: 15 AN: 251360 Hom.: 0 AF XY: 0.0000442 AC XY: 6 AN XY: 135866

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000114

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000228 AC: 331 AN: 1450660 Hom.: 0 Cov.: 28 AF XY: 0.000206 AC XY: 149 AN XY: 722506

Gnomad4 AFR exome AF: 0.000121

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000293

Gnomad4 OTH exome AF: 0.0000666

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152144 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74324

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000819 Hom.: 0

Bravo AF: 0.0000151

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000519 AC: 2

ExAC AF: 0.0000247 AC: 3

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:31 Other:2

Revision: reviewed by expert panel

Submissions by phenotype

Familial cancer of breast Pathogenic:9

Pathogenic, criteria provided, single submitter	clinical testing	Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	Jul 11, 2022	PVS1, PS4 -
Pathogenic, criteria provided, single submitter	clinical testing	Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	Apr 03, 2017	This c.3113G>A (p.Trp1038*) variant has previously been reported in 16 (out of 4,178 total) patients with breast cancer [PMID 17200668, 21285249, 25575445, 23448497, 26283626, 21409391, 23471749]. The cumulative risk for carrier of this variant was estimated as 91% by age 70 with a median age of onset of 42 years old reported in an Australian population [PMID 23471749]. This c.3113G>A is located in exon 10 of the PALB2 gene at the exon/intron junction with intron 10. Transcripts analysis showed that this variant not only produces a stop codon at amino acid position 1038 but also produces two additional PALB2 transcripts including an alternative splicing and a complete deletion of exon 10, all three leading to a loss of function of the protein [PMID 23471749]. The c.3113G>A (p.Trp1038*) variant has been observed in two Europeans and one African individual at the heterozygous state in the ExAC population database (http://exac.broadinstitute.org/variant/16-23632683-C-T). It is thus interpreted as a pathogenic variant. -
Likely pathogenic, criteria provided, single submitter	case-control	Cancer Genetics Laboratory, Peter MacCallum Cancer Centre	Jun 01, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Mar 18, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 29, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Mar 31, 2023	This variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation. -
Pathogenic, reviewed by expert panel	curation	ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer Variant Curation Expert Panel, ClinGen	Apr 05, 2023	The c.3113G>A (p.Trp1038Ter) variant in PALB2 occurs at the last nucleotide of exon 10. It is predicted to cause skipping of biologically-relevant exon 10, as well as partial deletion of exon 10, resulting in a frameshift leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism. This prediction is confirmed by RT-PCR analysis (PMID: 21285249, 23448497). This alteration results in a termination codon upstream of the most C-terminus pathogenic alteration (PALB2 p.Tyr1183*), as classified by the HBOP VCEP, and is expected to be more deleterious. This variant is non-functional in multiple different protein assays (PMID 31757951); however due to a lack of positive missense controls with known clinical impact, these protein assays do not meet the requirements for use by the HBOP VCEP. The prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls [OR=4.21, 95% CI:1.84 - 9.60] (PMID: 27595995). The highest population filtering allele frequency in gnomAD v2.1.1 is 0.00006665 in the European (Non-Finnish) population (PM2_Supporting, BS1, and BA1 are not met). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant hereditary breast and pancreatic cancer and autosomal recessive FANCN based on the ACMG/AMP criteria applied, as specified by the HBOP VCEP. (PVS1(RNA), PS4, PM5_Supporting). -
Pathogenic, no assertion criteria provided	clinical testing	Pathway Genomics	Nov 06, 2014	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	This sequence change creates a premature translational stop signal (p.Trp1038*) in the PALB2 gene. RNA analysis indicates that this premature translational stop signal induces altered splicing and may result in an absent or disrupted protein product. This variant is present in population databases (rs180177132, gnomAD 0.01%). This premature translational stop signal has been observed in individual(s) with breast cancer (PMID: 17200668, 21182766, 21285249, 23471749). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 126711). Studies have shown that this premature translational stop signal results in activation of a cryptic splice site and introduces a premature termination codon (Invitae). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic. -

not provided Pathogenic:7

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Feb 11, 2020	Observed in multiple individuals with a personal and/or family history of breast cancer and is considered a pathogenic founder variant in the British population (Rahman 2007, Southey 2010, Wong 2011, Teo 2013, Hartley 2014, Southey 2016, Winship 2016); Published functional studies demonstrate a damaging effect: reduced RAD51 foci formation, abnormal cellular localization, diminished homology repair efficiency, weak protein expression (Pauty 2017, Boonen 2019); This variant is associated with the following publications: (PMID: 21165770, 17200668, 21409391, 23471749, 18302019, 19264984, 22241545, 26283626, 24206657, 25099575, 19763819, 26250988, 23787919, 23448497, 26786923, 27621404, 25575445, 28158555, 32081490, 32581362, 25525159, 25225577, 24415441, 23935381, 21932393, 24870022, 20346647, 24556926, 24136930, 24061862, 26534844, 25356972, 17200671, 21182766, 21285249, 26787237, 27547810, 27595995, 28019080, 28135136, 27099641, 26985847, 27296296, 27433846, 26681312, 26315354, 28864920, 28779002, 29431189, 29909963, 30665703, 29961768, 30322717, 31090900, 31757951, 31263054, 29625052, 26689913, 32426482, 31447099, 32832836, 32338768) -
Pathogenic, no assertion criteria provided	curation	Leiden Open Variation Database	Sep 30, 2019	Curators: Marc Tischkowitz, Arleen D. Auerbach. Submitters to LOVD: James Whitworth, kConFab - Heather Thorne, Marc Tischkowitz. -
Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Jul 23, 2024	PM5_supporting, PS4, PVS1 -
Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Sep 30, 2019	This nonsense variant causes the premature termination of PALB2 protein synthesis. In the published literature, the variant has been reported in one healthy individual, in a control group, and in individuals affected with breast or prostate cancer (PMIDs: 30665703 (2019), 27433846 (2016), 26283626 (2015), 25225577 (2014), and 21182766 (2010)). Additionally, splicing studies have shown that this variant produces three alternate transcripts which either result in premature termination of protein synthesis or deletion of exon 10 (PMIDs: 23471749 (2013) and 21285249 (2011)). Based on this information, this variant is classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Jan 15, 2021	DNA sequence analysis of the PALB2 gene demonstrated a sequence change, c.3113G>A, located in the consensus splice site of the exon. Functional studies have demonstrated that this sequence change affects normal splicing and creates different PALB2 transcripts in lymphoblastoid cells derived from individuals with breast cancer, including one with complete skipping of exon 10 (deletion of 117 bp), another with an alternative splice site within exon 10 (out-of-frame deletion of 31 bp), and one which results in an immediate stop at amino acid position 1038 (p.Trp1038*) (PMID: 21285249, 23448497). The p.Trp1038* change has been reported in individuals and families with breast cancer, with evidence of co-segregation with disease (PMID: 17200668, 21182766, 21285249, 23471749). This sequence change has been observed in the gnomAD database with a frequency of 0.011% in the European sub-population (dbSNP rs180177132). These collective evidences suggest that this sequence change is pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	AiLife Diagnostics, AiLife Diagnostics	Feb 09, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Mar 06, 2018	- -

Hereditary cancer-predisposing syndrome Pathogenic:5

Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jan 17, 2024	This variant causes a nonsense mutation in exon 10 and is also predicted to disrupt splicing at the intron 10 splice donor site in the PALB2 gene. RNA studies have reported that this variant causes splicing defects resulting in an in-frame deletion of exon 10 or exons 9 and 10, impacting the WD40 domain of PALB2, or an out-of-frame transcript due to the use of a cryptic donor site within exon 10 that results in a premature translational stop signal. Normally spliced transcript from the mutant allele has a nonsense mutation due to the coding sequence change (PMID: 21285249, 23448497, 31843900). This variant has been observed in over a dozen individuals affected with early-onset breast cancer with positive history of breast and other cancers (PMID: 17200668, 21182766, 21285249, 22241545, 23471749, 25225577, 28864920; DOI: 10.1016/j.gimo.2023.100849), an individual affected with familial pancreatic cancer (PMID: 25356972), and in two individuals affected with ovarian cancer and two unaffected individuals (PMID: 26315354). This variant has been detected in a breast cancer case-control meta-analysis in 31/60466 cases and 6/53461 unaffected individuals with an estimated odds ratio of 4.57 (95% CI 1.906 to 10.955) (PMID: 33471991; Leiden Open Variation Database DB-ID PALB2_010150). This variant has been shown to segregate with breast cancer in families (PMID: 21182766, 26534844). This variant has been identified in 17/282756 chromosomes in the general population by the Genome Aggregation Database (gnomAD), predominantly in non-Finnish Europeans and also in African-Americans. Loss of PALB2 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	research	Academic Department of Medical Genetics, University of Cambridge	Jan 26, 2018	Application of AMCG guidelines 2015. Used other ClinVar submission evidence where relevant. Loss of heterozygosity in tumours or immunohistochemistry abnormalities considered functional evidence of pathogenicity. -
Pathogenic, criteria provided, single submitter	clinical testing	University of Washington Department of Laboratory Medicine, University of Washington	Nov 20, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Oct 26, 2022	The c.3113G>A pathogenic mutation (also known as p.W1038*), located in coding exon 10 of the PALB2 gene, results from a G to A substitution at nucleotide position 3113. This changes the amino acid from a tryptophan to a stop codon within coding exon 10. This change occurs in the last base pair of coding exon 10, and has been shown to generate three aberrant mRNA isoforms: one with complete skipping of exon 10 (deletion of 117 bp), another which uses an alternative splice site within exon 10 (out-of-frame deletion of 31 bp) (Casadei S et al. Cancer Res. 2011 Mar;71:2222-9; Teo ZL et al. Breast Cancer Res. 2013 Feb;15:R17; Casadei S et al. Proc Natl Acad Sci U S A, 2019 Dec). In addition, this mutation has been identified in multiple early-onset breast cancer probands with significant breast cancer family histories (Hartley T et al. Hered Cancer Clin Pract. 2014;12:19; Teo ZL et al. Fam. Cancer. 2013 Dec;12:587-95; Rahman N et al. Nat. Genet. 2007 Feb;39:165-7; Wong MW et al. Breast Cancer Res. Treat. 2011 Jun;127:853-9; Zhen DB et al. Genet. Med. 2015 Jul;17:569-77; Nguyen-Dumont T et al. Breast Cancer Res. Treat. 2015 Jan;149:547-54; Thompson ER et al. Breast Cancer Res. 2015 Aug;17:111; Ding YC et al. Fam. Cancer. 2018 Apr;17:187-195). This alteration has also been reported in a kindred with at least two family members affected with pancreatic cancer (Zhen DB et al. Genet. Med. 2015 Jul;17:569-77). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. -
Pathogenic, criteria provided, single submitter	clinical testing	Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	Aug 01, 2023	- -

PALB2-related disorder Pathogenic:2

Pathogenic, no assertion criteria provided	clinical testing	PreventionGenetics, part of Exact Sciences	Aug 30, 2024	The PALB2 c.3113G>A variant is predicted to result in premature protein termination (p.Trp1038*). This variant has been reported in multiple individuals with a personal and/or family history of breast cancer (Rahman et al. 2007. PubMed ID: 17200668; Southey et al. 2010. PubMed ID: 21182766; Teo et al. 2013. PubMed ID: 23448497; Teo et al. 2013. PubMed ID: 23471749; Hartley et al. 2014. PubMed ID: 25225577). Functional studies showed that this variant alters splicing and results in three different mRNA transcripts (Casadei et al. 2011. PubMed ID: 21285249). This variant is reported in 0.012% of alleles in individuals of African descent in gnomAD and is interpreted as pathogenic in ClinVar by the ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer Variant Curation Expert Panel (https://www.ncbi.nlm.nih.gov/clinvar/variation/126711/). Nonsense variants in PALB2 are expected to be pathogenic. This variant is interpreted as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Sep 19, 2018	The PALB2 c.3113G>A (p.Trp1038Ter) variant is a stop-gained variant that is predicted to result in a premature termination of the protein. Across a selection of the available literature, the c.3113G>A (p.Trp1038Ter) variant has been identified in a heterozygous state in at least 21 probands from 13 unrelated families (Rahman et al. 2007; Southey et al. 2010; Teo et al. 2013; Hartley et al. 2014). Affected individuals were found to have a variety of cancers including breast, ovarian, and pancreatic. The p.Trp1038Ter variant was absent from 1724 healthy control subjects and is reported at a frequency of 0.000125 in the African population of the Genome Aggregation Database. Experimental studies on RNA isolated from patient derived lymphoblastoid cell lines have shown that the p.Trp1038Ter variant caused altered splicing (Casadei et al. 2011; Teo et al. 2013). Although this variant has not been reported in any probands with Fanconi anemia, it is known that PALB2 heterozygous variants can also confer carrier status for Fanconi anemia. Due to the potential impact of stop-gained variants and the evidence from the literature, this variant is classified as pathogenic for PALB2-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -

Inherited breast cancer and ovarian cancer Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	NHS Central & South Genomic Laboratory Hub	Nov 12, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genomics and Molecular Medicine Service, East Genomic Laboratory Hub, NHS Genomic Medicine Service	May 14, 2024	PVS1,PS4 -

Breast and/or ovarian cancer Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Sep 13, 2022

- -

Breast-ovarian cancer, familial, susceptibility to, 5 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Nov 13, 2023

A known pathogenic mutation was detected in the PALB2 gene (c.3113G>A).This sequence change creates a premature translational stop signal (p.Trp1038*) in the PALB2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in PALB2 are known to be pathogenic (PMID: 17200668, 17200671, 17200672, 24136930, 25099575). This variant is present in population databases (rs180177132, gnomAD 0.01%). This premature translational stop signal has been observed in individual(s) with breast cancer (PMID: 21165770, 17200668, 21409391, 23471749, 18302019, 19264984, 22241545, 26283626, 24206657, 25099575, 19763819, 26250988, 23787919, 23448497, 26786923, 27621404, 25575445, 28158555, 32081490, 32581362, 25525159, 25225577, 24415441, 23935381, 21932393, 24870022, 20346647, 24556926, 24136930, 24061862, 26534844, 25356972, 17200671, 21182766, 21285249, 26787237, 27547810, 27595995, 28019080, 28135136, 27099641, 26985847, 27296296, 27433846, 26681312, 26315354, 28864920, 28779002, 29431189, 29909963, 30665703, 29961768, 30322717, 31090900, 31757951, 31263054, 29625052, 26689913, 32426482, 31447099, 32832836, 32338768) . It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 126711). Published functional studies demonstrate a damaging effect, abnormal cellular localization, diminished homology repair efficiency, weak protein expression (PMID: 21285249, 23448497). For these reasons, this variant has been classified as Pathogenic. -

NICE approved PARP inhibitor treatment Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Cambridge Genomics Laboratory, East Genomic Laboratory Hub, NHS Genomic Medicine Service

Apr 30, 2024

PVS1,PS4 -

Inherited ovarian cancer (without breast cancer) Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Genomics and Molecular Medicine Service, East Genomic Laboratory Hub, NHS Genomic Medicine Service

May 03, 2024

PVS1,PS4 -

Hereditary cancer-predisposing syndrome;C0346153:Familial cancer of breast Pathogenic:1

Pathogenic, no assertion criteria provided

research

King Laboratory, University of Washington

Sep 01, 2019

- -

Hereditary breast ovarian cancer syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

May 08, 2017

- -

Breast cancer, susceptibility to Other:1

risk factor, no assertion criteria provided

literature only

OMIM

Feb 28, 2013

- -

Malignant tumor of breast;C1835817:Fanconi anemia complementation group N;C3150547:Pancreatic cancer, susceptibility to, 3 Other:1

not provided, no classification provided

phenotyping only

GenomeConnect - Invitae Patient Insights Network

-

Variant interpreted as Pathogenic and reported on 04-13-2020 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.44	D
BayesDel_noAF	Pathogenic	0.60
CADD	Pathogenic	54
DANN	Uncertain	0.99
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.87
FATHMM_MKL	Uncertain	0.90	D
MutationTaster	Benign	1.0	A
Vest4		0.90
GERP RS		5.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.99
SpliceAI score (max)		0.74		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.74		Position offset: 0

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs180177132; hg19: chr16-23632683; COSMIC: COSV104552889; COSMIC: COSV104552889;