rs786202782

chr17-31223475-TTAAC-T

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PVS1 PM2 PP5

The NM_001042492.3(NF1):c.1756_1759del(p.Thr586ValfsTer18) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. L585L) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: NF1 NM_001042492.3 frameshift
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:21 U:1
• Conservation: PhyloP100: 8.63

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]

ACMG classification

Verdict is Pathogenic. Variant got 11 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 17-31223475-TTAAC-T is Pathogenic according to our data. Variant chr17-31223475-TTAAC-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 186215.We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=18, Uncertain_significance=1}. Variant chr17-31223475-TTAAC-T is described in Lovd as [Pathogenic]. Variant chr17-31223475-TTAAC-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NF1	NM_001042492.3	c.1756_1759del	p.Thr586ValfsTer18	frameshift_variant	16/58	ENST00000358273.9
NF1	NM_000267.3	c.1756_1759del	p.Thr586ValfsTer18	frameshift_variant	16/57

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NF1	ENST00000358273.9	c.1756_1759del	p.Thr586ValfsTer18	frameshift_variant	16/58	1	NM_001042492.3	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251120 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135734

Gnomad AFR exome AF: 0.00

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: 0.00000881

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000137 AC: 2 AN: 1460698 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 726710

Gnomad4 AFR exome AF: 0.00

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: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:21 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Neurofibromatosis, type 1 Pathogenic:9 Uncertain:1

Pathogenic, criteria provided, single submitter	clinical testing	Centre for Mendelian Genomics, University Medical Centre Ljubljana	May 31, 2019	This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PVS1,PS1,PS3,PP4. -
Uncertain significance, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	Mar 29, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Nov 21, 2023	Criteria applied: PVS1,PS3,PS4_MOD,PM2_SUP -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 08, 2024	This sequence change creates a premature translational stop signal (p.Thr586Valfs*18) in the NF1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in NF1 are known to be pathogenic (PMID: 10712197, 23913538). This variant is present in population databases (rs786202782, gnomAD 0.0009%). This premature translational stop signal has been observed in individual(s) with neurofibromatosis type 1 (PMID: 9783703, 16835897, 17311297, 18546366, 25788518). ClinVar contains an entry for this variant (Variation ID: 186215). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Mar 15, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genomic Research Center, Shahid Beheshti University of Medical Sciences	Jun 18, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Center for Human Genetics, Inc, Center for Human Genetics, Inc	Nov 01, 2016	- -
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	3billion	May 22, 2022	The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: <0.001%). Frameshift: predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant. The variant has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000186215). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. -
Pathogenic, criteria provided, single submitter	clinical testing	Medical Genetics, University of Parma	Dec 20, 2019	- -

not provided Pathogenic:7

Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Dec 29, 2017	This frameshift variant alters the translational reading frame of the NF1 mRNA and causes the premature termination of NF1 protein synthesis. The frequency of this variant in the general population, 0.000004 (1/251120 chromosomes, http://gnomad.broadinstitute.org), is consistent with pathogenicity. In the published literature, the variant has been reported in individuals with neurofibromatosis 1 (PMID: 31776437 (2020), 32533764 (2020), 34080803 (2021), 34080803 (2022)). A functional study found this variant results in reduced neurofibromin expression compared to wild type (PMID: 25788518 (2015)). Based on the available information, this variant is classified as pathogenic. -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Dec 29, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Nov 22, 2021	Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Published functional studies demonstrate a damaging effect: variant results in reduced neurofibromin expression and increased RAS activity compared to wild type (Park 1998, Anatasaki 2015); This variant is associated with the following publications: (PMID: 17311297, 9783703, 26514327, 29618358, 28955729, 12807981, 16835897, 18546366, 23906300, 25788518, 28068329, 23758643, 31766501, 31533651, 31476437, 31717729, 32056211, 29625052, 32533764, 31776437) -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2021	- -
Pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	Mar 08, 2021	PVS1, PS4, PM2_Supporting, PM6 -

Inborn genetic diseases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 10, 2023

The c.1756_1759delACTA (p.T586Vfs*18) alteration, located in exon 16 (coding exon 16) of the NF1 gene, consists of a deletion of 4 nucleotides from position 1756 to 1759, causing a translational frameshift with a predicted alternate stop codon after 18 amino acids. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. This allele was reported in one heterozygous individual in population-based cohorts in the Genome Aggregation Database (gnomAD). This alteration has been reported in multiple individuals diagnosed with NF1, both sporadic and familial (Park, 1998; Fahsold, 2000; Ars, 2003; Hüffmeier, 2006; Wimmer, 2007; Yap, 2016; Anastasaki, 2017; Melloni, 2019; Yao, 2019; Kang, 2020; Peces, 2020; N Abdel-Aziz, 2021; Riva, 2022). Based on the available evidence, this alteration is classified as pathogenic. -

NF1-related disorder Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 19, 2023

The NF1 c.1756_1759delACTA variant is predicted to result in a frameshift and premature protein termination (p.Thr586Valfs*18). This variant was reported in individuals with Neurofibromatosis 1 (see for example - Park et al. 1998. PubMed ID: 9783703; Anastasaki et al. 2015. PubMed ID: 25788518; Corsello et al. 2018. PubMed ID: 29618358). This variant is reported in 0.00088% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/17-29550493-TTAAC-T) and is interpreted as pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/186215/). Frameshift variants in NF1 are expected to be pathogenic. This variant is interpreted as pathogenic. -

Juvenile myelomonocytic leukemia Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

May 25, 2023

- -

Neurofibroma Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Department of Ophthalmology, Shanghai Ninth people hospital, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University

Jun 29, 2019

- -

Hereditary cancer-predisposing syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 12, 2015

Thec.1756_1759delACTApathogenic mutation, located in codingexon16 of theNF1gene, results from a deletion of 4 nucleotides between nucleotide positions 1756 and 1759, causing a translational frameshift with a predicted alternate stop codon. This mutation has been reported in multiple individuals diagnosed with NF1, both sporadic and familial (Yap P et al. PediatrBlood Cancer. 2015 Oct; [epub ahead of print]; Wimmer K et al. HumMutat. 2007 Jun;28(6):599-612; Ars E et al. J Med Genet. 2003 Jun;40(6):e82; Park VM et al. J Med Genet. 1998 Oct;35(10):813-20). In one functional study, this mutation was reported in a 26 year old female with a clinical diagnosis of NF1, who was found to have 20% neurofibromin expression in fibroblasts (Anastasaki C et al. Hum. Mol. Genet. 2015 Jun; 24(12):3518-28). In addition to the clinical data presented in the literature, sinceframeshiftsare typically deleterious in nature, this alteration is interpreted as a disease-causing mutation (ACMG Recommendations for Standards for Interpretation and Reporting of Sequence Variations. Revision 2007. Genet Med. 2008;10:294). -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs786202782; hg19: chr17-29550493;