17-31232869-A-G

Position:

chr17-31232869-A-G

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 1P and 4B. PP2BP4_ModerateBP6BS2_Supporting

The NM_001042492.3(NF1):c.3484A>G(p.Met1162Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000018 in 1,614,036 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000039 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000016 ( 0 hom. )

Consequence

NF1
NM_001042492.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:5

Conservation

PhyloP100: 8.88

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:

NF1 (HGNC:):

NF1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -3 ACMG points.

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), NF1. . Gene score misZ 6.5427 (greater than the threshold 3.09). Trascript score misZ 8.4054 (greater than threshold 3.09). GenCC has associacion of gene with neurofibromatosis, familial spinal, hereditary pheochromocytoma-paraganglioma, neurofibromatosis type 1, Watson syndrome, neurofibromatosis-Noonan syndrome, Moyamoya disease, familial ovarian cancer.

BP4

Computational evidence support a benign effect (MetaRNN=0.100688875).

BP6

Variant 17-31232869-A-G is Benign according to our data. Variant chr17-31232869-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 219750.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=1, Benign=2}.

BS2

High AC in GnomAd4 at 6 AD gene. Variant has AC lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NF1	NM_001042492.3 linkuse as main transcript	c.3484A>G	p.Met1162Val	missense_variant	26/58	ENST00000358273.9	NP_001035957.1	P21359-1
NF1	NM_000267.3 linkuse as main transcript	c.3484A>G	p.Met1162Val	missense_variant	26/57		NP_000258.1	P21359-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NF1	ENST00000358273.9 linkuse as main transcript	c.3484A>G	p.Met1162Val	missense_variant	26/58	1	NM_001042492.3	ENSP00000351015.4		P21359-1

Frequencies

GnomAD3 genomes

AF:

0.0000394

AC:

AN:

152184

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00115

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

GnomAD3 exomes

AF:

0.000111

AC:

AN:

251296

Hom.:

AF XY:

0.000118

AC XY:

AN XY:

135800

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00147

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000880

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000157

AC:

AN:

1461852

Hom.:

Cov.:

AF XY:

0.0000138

AC XY:

AN XY:

727230

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000504

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000270

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000394

AC:

AN:

152184

Hom.:

Cov.:

AF XY:

0.0000673

AC XY:

AN XY:

74344

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00115

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000712

Hom.:

Bravo

AF:

0.0000793

ExAC

AF:

0.0000906

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:5

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Hereditary cancer-predisposing syndrome

Uncertain:1Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Jun 25, 2015	The p.M1162V variant (also known as c.3484A>G), located in coding exon 26 of the NF1 gene, results from an A to G substitution at nucleotide position 3484. The methionine at codon 1162 is replaced by valine, an amino acid with highly similar properties. This variant was not reported in population based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project. In the ESP, this variant was not observed in 6503 samples (13006 alleles) with coverage at this position. To date, this alteration has been detected with an allele frequency of approximately 0.002% (greater than 55000alleles tested) in our clinical cohort.This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive.Since supporting evidence is limited at this time, the clinical significance of p.M1162Vremains unclear. -
Likely benign, criteria provided, single submitter	curation	Sema4, Sema4	May 30, 2021	- -

not provided

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

The NF1 p.M1162V variant was identified in one of 200 proband chromosomes (frequency: 0.005) from individuals or families with a clinical diagnosis of Neurofibromatosis type 1 (NF1) (Wu-Chou_2018_PMID:30290804). The variant was also identified in one of 34 proband chromosomes (frequency: 0.029) from individuals with a clinical diagnosis of Noonan syndrome (Koh_2019_PMID:30784236). This patient inherited the p.M1162V variant from his father and both did not meet clinical criteria for NF1 (Koh_2019_PMID:30784236). The variant was also identified in dbSNP (ID: rs773968270) and in ClinVar (conflicting interpretations of pathogenicity; classified as uncertain significance by Ambry Genetics and likely benign by Invitae for Neurofibromatosis type 1 and Hereditary cancer-predisposing syndrome). The variant was not identified in COSMIC or LOVD 3.0. The variant was identified in control databases in 32 of 282690 chromosomes at a frequency of 0.000113 (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: East Asian in 31 of 19924 chromosomes (freq: 0.001556) and European (non-Finnish) in 1 of 129068 chromosomes (freq: 0.000008), but was not observed in the African, Latino, Ashkenazi Jewish, European (Finnish), Other, or South Asian populations. The p.Met1162 residue is conserved in mammals but not in more distantly related organisms however four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. -

not specified

Benign:1

Likely benign, no assertion criteria provided

clinical testing

Genetic Services Laboratory, University of Chicago

Jul 13, 2022

- -

Ovarian cancer

Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory of Molecular Epidemiology of Birth Defects, West China Second University Hospital, Sichuan University

Jan 01, 2022

- -

Neurofibromatosis, type 1

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 28, 2024

- -

Hereditary cancer-predisposing syndrome;CN230736:Cardiovascular phenotype

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 30, 2021

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.17

BayesDel_addAF

Benign

-0.14

BayesDel_noAF

Uncertain

-0.010

CADD

Benign

DANN

Benign

0.95

DEOGEN2

Uncertain

0.63

D;.;T

Eigen

Benign

0.12

Eigen_PC

Uncertain

0.31

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.92

D;D;D

M_CAP

Pathogenic

0.47

MetaRNN

Benign

0.10

T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.17

N;N;.

PrimateAI

Pathogenic

0.88

PROVEAN

Benign

-2.2

N;N;N

REVEL

Uncertain

0.39

Sift

Benign

0.40

T;T;T

Sift4G

Benign

0.61

T;T;T

Polyphen

0.013

B;B;.

Vest4

0.92

MutPred

0.34

Gain of sheet (P = 0.0344);Gain of sheet (P = 0.0344);.;

MVP

0.86

MPC

1.1

ClinPred

0.14

GERP RS

5.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.26

gMVP

0.64

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

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