chr17-31225143-T-A

Variant names:

Variant summary

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

The NM_001042492.3(NF1):c.1894T>A(p.Cys632Ser) variant causes a missense change. The variant allele was found at a frequency of 0.0000124 in 1,613,664 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000046 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000089 ( 0 hom. )

Consequence

NF1
NM_001042492.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:8B:3O:1

Conservation

PhyloP100: 4.23

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 Likely_benign. Variant got -3 ACMG points.

PP2

Missense variant in the NF1 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 399 curated pathogenic missense variants (we use a threshold of 10). The gene has 143 curated benign missense variants. Gene score misZ: 6.5427 (above the threshold of 3.09). Trascript score misZ: 8.4054 (above the threshold of 3.09). GenCC associations: The gene is linked to 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=0.13229391).

BP6

Variant 17-31225143-T-A is Benign according to our data. Variant chr17-31225143-T-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 134883.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=8, not_provided=1}.

BS2

High AC in GnomAd4 at 7 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 rank	MANE	Protein	UniProt
NF1	NM_001042492.3 link	c.1894T>A	p.Cys632Ser	missense_variant	Exon 17 of 58	ENST00000358273.9	NP_001035957.1	P21359-1
NF1	NM_000267.3 link	c.1894T>A	p.Cys632Ser	missense_variant	Exon 17 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.1894T>A	p.Cys632Ser	missense_variant	Exon 17 of 58	1	NM_001042492.3	ENSP00000351015.4		P21359-1

Frequencies

GnomAD3 genomes

AF:

0.0000460

AC:

AN:

152150

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

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:

0.0000735

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000199

AC:

AN:

251236

Hom.:

AF XY:

0.0000295

AC XY:

AN XY:

135766

show subpopulations

Gnomad AFR exome

AF:

0.0000615

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:

0.0000352

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000889

AC:

AN:

1461514

Hom.:

Cov.:

AF XY:

0.0000110

AC XY:

AN XY:

727068

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:

0.0000117

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000460

AC:

AN:

152150

Hom.:

Cov.:

AF XY:

0.0000538

AC XY:

AN XY:

74326

show subpopulations

Gnomad4 AFR

AF:

0.0000483

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:

0.0000735

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000169

Hom.:

Bravo

AF:

0.0000529

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.0000330

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:8Benign:3Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Neurofibromatosis, type 1

Uncertain:2Benign:1

Mar 22, 2019

Baylor Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -

Mar 15, 2022

Genome-Nilou Lab

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 29, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Uncertain:2Benign:1

Oct 10, 2024

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The NF1 c.1894T>A (p.Cys632Ser) variant has been reported in the published literature in individuals with breast cancer (PMID: 33471991 (2021), see also LOVD (http://databases.lovd.nl/shared/)), in an individual with an unspecified advanced cancer (PMID: 28873162 (2017)), as well as in reportedly healthy individuals (PMID: 24728327 (2014) and 33471991 (2021), see also LOVD (http://databases.lovd.nl/shared/)). The frequency of this variant in the general population, 0.000047 (6/128992 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is benign. Based on the available information, we are unable to determine the clinical significance of this variant. -

Mar 07, 2018

Athena Diagnostics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 25, 2023

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

See Variant Classification Assertion Criteria. -

Hereditary cancer-predisposing syndrome

Uncertain:2

Feb 22, 2016

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.C632S variant (also known as c.1894T>A), located in coding exon 17 of the NF1 gene, results from a T to A substitution at nucleotide position 1894. The cysteine at codon 632 is replaced by serine, an amino acid with dissimilar properties.This alteration was previously reported in 1/681 individuals in a healthy, ancestrally diverse cohort via genome sequencing, having been detected in 1/331European individuals in this cohort (BodianDL et al.PLoSONE2014;9(4):e94554). This variant was previously reported in the SNPDatabase as rs370789267. Based on data from the NHLBI Exome Sequencing Project (ESP), the A allele has an overall frequency of approximately 0.01% (1/13006) total alleles studied, having been observed in0.01% (1/8600) European American alleles. To date, this alteration has been detected with an allele frequency of approximately 0.004% (greater than 110000 alleles tested) in our clinical cohort. This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of p.C632S remains unclear. -

Mar 10, 2022

Sema4, Sema4

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: curation

- -

not specified

Uncertain:1Other:1

Sep 19, 2013

ITMI

Significance: not provided

Review Status: no classification provided

Collection Method: reference population

- -

Aug 09, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: NF1 c.1894T>A (p.Cys632Ser) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 2.4e-05 in 251898 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.1894T>A in individuals affected with Neurofibromatosis Type 1 and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 134883). Based on the evidence outlined above, the variant was classified as uncertain significance. -

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

Uncertain:1

Nov 10, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary cancer-predisposing syndrome;CN230736:Cardiovascular phenotype

Benign:1

Mar 24, 2023

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely 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

0.12

BayesDel_addAF

Benign

-0.20

BayesDel_noAF

Benign

-0.34

CADD

Benign

DANN

Benign

0.25

DEOGEN2

Uncertain

0.45

T;.;T

Eigen

Benign

-0.33

Eigen_PC

Benign

-0.12

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Benign

0.68

T;T;T

M_CAP

Benign

0.075

MetaRNN

Benign

0.13

T;T;T

MetaSVM

Benign

-0.92

MutationAssessor

Benign

0.69

N;N;.

PrimateAI

Benign

0.43

PROVEAN

Benign

-0.51

N;N;N

REVEL

Benign

0.13

Sift

Benign

0.82

T;T;T

Sift4G

Benign

0.82

T;T;T

Polyphen

0.0040

B;B;.

Vest4

0.81

MutPred

0.44

Gain of disorder (P = 0.0059);Gain of disorder (P = 0.0059);.;

MVP

0.57

MPC

0.85

ClinPred

0.062

GERP RS

5.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.15

gMVP

0.30

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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