rs267606599

Positions:

• chr17-31230383-G-A
• chr17-31230383-G-C
• chr17-31230383-G-T

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1_Moderate PM2 PP5_Very_Strong

The NM_001042492.3(NF1):​c.3113+1G>A variant causes a splice donor, intron change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,084 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: NF1 NM_001042492.3 splice_donor, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:14
• Conservation: PhyloP100: 9.56

Genes affected

NF1 (HGNC:7765): (neurofibromin 1) This gene product appears to function as a negative regulator of the ras signal transduction pathway. Mutations in this gene have been linked to neurofibromatosis type 1, juvenile myelomonocytic leukemia and Watson syndrome. The mRNA for this gene is subject to RNA editing (CGA>UGA->Arg1306Term) resulting in premature translation termination. Alternatively spliced transcript variants encoding different isoforms have also been described for this gene. [provided by RefSeq, Jul 2008]

NF1 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 12 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.0143192485 fraction of the gene. No cryptic splice site detected. Exon removal is inframe change.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 17-31230383-G-A is Pathogenic according to our data. Variant chr17-31230383-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 345.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-31230383-G-A is described in Lovd as [Pathogenic]. Variant chr17-31230383-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NF1	NM_001042492.3	c.3113+1G>A		splice_donor_variant, intron_variant		ENST00000358273.9	NP_001035957.1
NF1	NM_000267.3	c.3113+1G>A		splice_donor_variant, intron_variant			NP_000258.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NF1	ENST00000358273.9	c.3113+1G>A		splice_donor_variant, intron_variant		1	NM_001042492.3	ENSP00000351015.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000399 AC: 1 AN: 250808 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135668

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

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: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461084 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 726834

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000468 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:14

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Neurofibromatosis, type 1 Pathogenic:9

Pathogenic, criteria provided, single submitter	clinical testing	Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India	-	This variant is reported in the ClinVar database as pathogenic by 13 submitters (Accession ID: VCV000000345.39). This canonical splice-site variant is likely to result in aberrant splicing leading to either formation of a truncated protein product or the transcript to undergo nonsense-mediated mRNA decay. -
Pathogenic, criteria provided, single submitter	clinical testing	Centre for Mendelian Genomics, University Medical Centre Ljubljana	Apr 02, 2020	This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PVS1,PS3,PS4. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Apr 01, 1995	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Sep 25, 2020	- -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Laboratory Sciences Program (CLSP), King Saud bin Abdulaziz University for Health Sciences (KSAU-HS)	Apr 01, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, The Hospital for Sick Children	Oct 26, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Mar 15, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	Aug 17, 2021	PVS1, PS3 -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 03, 2024	This sequence change affects a donor splice site in intron 23 of the NF1 gene. RNA analysis indicates that disruption of this splice site induces altered splicing and likely results in a shortened protein product. This variant is present in population databases (rs267606599, gnomAD 0.003%). Disruption of this splice site has been observed in individuals with neurofibromatosis, type 1 (PMID: 16944272, 18484666, 25293717, 26962827, 26969325). ClinVar contains an entry for this variant (Variation ID: 345). Studies have shown that disruption of this splice site results in skipping of exon 23, but is expected to preserve the integrity of the reading-frame (PMID: 7633431). For these reasons, this variant has been classified as Pathogenic. -

Neurofibromatosis, type 1;C4024216:Tibial pseudarthrosis Pathogenic:1

Pathogenic, criteria provided, single submitter

research

The Laboratory of Genetics and Metabolism, Hunan Children’s Hospital

Nov 10, 2018

- -

NF1-related disorder Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 30, 2024

The NF1 c.3113+1G>A variant is predicted to disrupt the GT donor site and interfere with normal splicing. This variant has been reported in multiple unrelated individuals with neurofibromatosis type 1 (see for example - Upadhyaya et al. 2008. PubMed ID: 18484666; Table S1 - Pros et al. 2008. PubMed ID: 18546366). Splicing studies found this variant results in skipping of exon 18 which is predicted to result in an inframe deletion (Table S1 - Pros et al. 2008. PubMed ID: 18546366). This variant is reported in 0.0029% of alleles in individuals of Latino descent in gnomAD. Variants that disrupt the consensus splice donor site in NF1 are expected to be pathogenic. This variant is interpreted as pathogenic. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Nov 16, 2021

Canonical splice site variant demonstrated to result in abnormal splicing leading to an in-frame deletion of a critical region (Purandare 1995); A different nucleotide change at this same canonical splice site (c.3113+1G>T) has been reported as pathogenic in ClinVar and at GeneDx (ClinVar SCV# SCV000253824.3; Landrum 2016); Also known as IVS18+1G>A; This variant is associated with the following publications: (PMID: 10712197, 25293717, 7633431, 16944272, 23913538, 26969325, 26962827, 18484666, 31370276, 31776437, 31533797) -

Hereditary cancer-predisposing syndrome;CN230736:Cardiovascular phenotype Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 10, 2021

The c.3113+1G>A intronic pathogenic mutation results from a G to A substitution one nucleotide after coding exon 23 of the NF1 gene. This mutation has been detected in multiple individuals who fulfilled diagnostic criteria for neurofibromatosis type 1 (Upadhyaya M et al. Hum. Mutat., 2008 Aug;29:E103-11; Thomas L et al. Eur. J. Hum. Genet., 2012 Apr;20:411-9; Emmerich D et al. Eur. J. Hum. Genet., 2015 Jun;23:870-3; Hutter S et al. Hum. Genet., 2016 May;135:469-75). In addition to the clinical data presented in the literature, RNA studies have demonstrated that the alteration results in skipping of exon 23, leading to an in-frame deletion in a region critical to protein function (Purandare SM et al. Hum. Mol. Genet., 1995 Apr;4:767-8; Ars E et al. J. Med. Genet., 2003 Jun;40:e82; Pros E et al. Hum. Mutat., 2008 Sep;29:E173-93; Ambry internal data). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Hereditary cancer-predisposing syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

curation

Sema4, Sema4

Mar 18, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.38	D
BayesDel_noAF	Pathogenic	0.39
CADD	Pathogenic	34
DANN	Uncertain	0.99
Eigen	Pathogenic	1.2
Eigen_PC	Pathogenic	1.0
FATHMM_MKL	Pathogenic	0.99	D
GERP RS		5.3

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.94
SpliceAI score (max)		1.0		Details are displayed if max score is > 0.2
DS_DL_spliceai		1.0		Position offset: -1

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

Publications

LitVar

Other links and lift over

dbSNP: rs267606599; hg19: chr17-29557401; COSMIC: COSV62207085; COSMIC: COSV62207085;