dbSNP rs876657715: NF1:p.Tyr2285fs (chr17-31338737-T-TA) – ACMG Classification: Pathogenic (18 pts)

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_001042492.3(NF1):c.6854dupA(p.Tyr2285fs) variant causes a frameshift, stop gained 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 (★★). 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 frameshift, stop_gained

Scores

Not classified

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:12

Conservation

PhyloP100: 8.62

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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 rank	MANE	Protein	UniProt
NF1	NM_001042492.3 link	c.6854dupA	p.Tyr2285fs	frameshift_variant, stop_gained	Exon 46 of 58	ENST00000358273.9	NP_001035957.1	P21359-1
NF1	NM_000267.3 link	c.6791dupA	p.Tyr2264fs	frameshift_variant, stop_gained	Exon 45 of 57		NP_000258.1	P21359-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NF1	ENST00000358273.9 link	c.6854dupA	p.Tyr2285fs	frameshift_variant, stop_gained	Exon 46 of 58	1	NM_001042492.3	ENSP00000351015.4		P21359-1

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

AN:

152160

Hom.:

Cov.:

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:

AN:

1461080

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

726886

show subpopulations

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:

AN:

152160

Hom.:

Cov.:

AF XY:

0.00

AC XY:

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:12

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Neurofibromatosis, type 1

Pathogenic:6

Mar 15, 2022

Genome-Nilou Lab

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 26, 2020

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 13, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Sep 28, 2021

MGZ Medical Genetics Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 28, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Nov 13, 2020

Institute of Human Genetics, University of Leipzig Medical Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Pathogenic:3

Nov 27, 2023

Clinical Genetics Laboratory, Skane University Hospital Lund

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 08, 2021

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

May 06, 2022

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Nov 10, 2018

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

Neurofibromatosis, type 1;C0349639:Juvenile myelomonocytic leukemia;C0553586:Café-au-lait macules with pulmonary stenosis;C1834235:Neurofibromatosis, familial spinal;C2931482:Neurofibromatosis-Noonan syndrome

Pathogenic:1

Juno Genomics, Hangzhou Juno Genomics, Inc

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PM2_Supporting+PVS1+PS4_Supporting+PP4 -

Hereditary cancer-predisposing syndrome;CN230736:Cardiovascular phenotype

Pathogenic:1

Aug 16, 2024

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 Nov;11; Zhu G et al. Orphanet J Rare Dis, 2019 Sep;14:221; Giugliano T et al. Genes (Basel), 2019 Jul;10:). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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

Name

Calibrated prediction

Score

Prediction

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over