rs876657715

chr17-31338737-T-TA

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_001042492.3(NF1):c.6854dup(p.Tyr2285Ter) variant causes a stop gained, frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,080 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. Y2285Y) has been classified as Uncertain significance. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.0 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: NF1 NM_001042492.3 stop_gained, frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:10
• Conservation: PhyloP100: 8.62

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 18 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 17-31338737-T-TA is Pathogenic according to our data. Variant chr17-31338737-T-TA is described in ClinVar as [Pathogenic]. Clinvar id is 228382.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NF1	NM_001042492.3	c.6854dup	p.Tyr2285Ter	stop_gained, frameshift_variant	46/58	ENST00000358273.9
NF1	NM_000267.3	c.6791dup	p.Tyr2264Ter	stop_gained, frameshift_variant	45/57

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NF1	ENST00000358273.9	c.6854dup	p.Tyr2285Ter	stop_gained, frameshift_variant	46/58	1	NM_001042492.3	P1

Frequencies

GnomAD3 genomes AF: 0.00 AC: 0 AN: 152160 Hom.: 0 Cov.: 32 FAILED QC

Gnomad AFR AF: 0.00

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: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461080 Hom.: 0 Cov.: 30 AF XY: 0.00000275 AC XY: 2 AN XY: 726886

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 Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 152160 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74336

Gnomad4 AFR AF: 0.00

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: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Neurofibromatosis, type 1 Pathogenic:6

Pathogenic, criteria provided, single submitter	clinical testing	MGZ Medical Genetics Center	Sep 28, 2021	- -
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	Institute of Human Genetics, University of Leipzig Medical Center	Nov 13, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Dec 21, 2023	This sequence change creates a premature translational stop signal (p.Tyr2264*) 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 not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individuals with neurofibromatosis type 1 (PMID: 8837715, 16941471, 17311297, 23913538, 24232412, 25325900, 27838393). This variant is also known as p.Tyr2285*. ClinVar contains an entry for this variant (Variation ID: 228382). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 28, 2016	The p.Tyr2285X variant in NF1 has been reported in >10 individuals with Neurofib romatosis I (NF1) (Upadhyaya 1996, Leiden Open Variation Database), 3 of which w ere apparently de novo. It was absent from large population studies, though the ability of these studies to accurately detect indels may be limited. This nonsen se variant leads to a premature termination codon at position 2285, which is pre dicted to lead to a truncated or absent protein. Heterozygous loss-of-function o f the NF1 gene is an established disease mechanism in NF1. In summary, this vari ant meets our criteria to be classified as pathogenic for NF1 in an autosomal do minant manner. -
Pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Mar 15, 2022	- -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Jan 08, 2021	The NF1 c.6854dupA;p.Tyr2285Ter variant (also known as c.6791dupA;p.Tyr2264Ter) is published in the medical literature in several individuals with a clinical diagnosis of neurofibromatosis type 1 (De Luca 2004, Maruoka 2014, Upadhyaya 1996). The variant is listed in the ClinVar database (Variation ID: 228382), but not in the dbSNP variant database or in the general population-based databases (Exome Variant Server, Genome Aggregation Database). This variant introduces a premature termination codon and is predicted to result in a truncated protein or mRNA subject to non-sense mediated decay. Considering available information, this variant is classified as pathogenic. References: De Luca A et al. Novel and recurrent mutations in the NF1 gene in Italian patients with neurofibromatosis type 1. Hum Mutat. 2004 Jun;23(6):629. Maruoka R et al. The use of next-generation sequencing in molecular diagnosis of neurofibromatosis type 1: a validation study. Genet Test Mol Biomarkers. 2014 Nov;18(11):722-35. Upadhyaya M et al. Characterization of six mutations in exon 37 of neurofibromatosis type 1 gene. Am J Med Genet. 1996 Jul 26;67(4):421-3. -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	May 06, 2022	Nonsense 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; Not observed in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 31370276, 10494088, 27322474, 27838393, 8837715, 15146469, 29566708, 29618358, 24232412, 16941471, 29914388, 30308447, 31533797, 32107864, 25325900, 31776437) -

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

- -

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

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 22, 2021

The c.6791dupA pathogenic mutation, located in coding exon 45 of the NF1 gene, results from a duplication of A at nucleotide position 6791, causing a translational frameshift with a predicted alternate stop codon (p.Y2264*). This alteration has been reported in multiple unrelated individuals with neurofibromatosis type 1 (Upadhyaya M et al. Am J Med Genet. 1996 Jul;67:421-3; Pros E et al. Hum Mutat. 2006 Nov;27:1104-14; Pros E et al. Hum Mutat. 2008 Sep;29:E173-93; Mao B et al. BMC Med Genet. 2018 06;19:101; Melloni G et al. Cancers (Basel). 2019 11;11; Zhu G et al. Orphanet J Rare Dis. 2019 09;14:221; Giugliano T et al. Genes (Basel). 2019 07;10). 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. -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs876657715; hg19: chr17-29665755;