chr17-31095346-G-T

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 4P and 2B. PM1PM2BP4_Moderate

The NM_001042492.3(NF1):c.37G>T(p.Val13Leu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V13A) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 30)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

NF1
NM_001042492.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.84

Publications

1 publications found

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:

MIR4733HG (HGNC:55332): (MIR4733 host gene)

MIR4733HG links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM1

In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 41 uncertain in NM_001042492.3

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.16394371).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NF1	NM_001042492.3 link	c.37G>T	p.Val13Leu	missense_variant	Exon 1 of 58	ENST00000358273.9	NP_001035957.1	P21359-1
NF1	NM_000267.4 link	c.37G>T	p.Val13Leu	missense_variant	Exon 1 of 57		NP_000258.1	P21359-2
NF1	NM_001128147.3 link	c.37G>T	p.Val13Leu	missense_variant	Exon 1 of 15		NP_001121619.1	P21359-5
MIR4733HG	NR_186435.1 link	n.145C>A		non_coding_transcript_exon_variant	Exon 1 of 4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NF1	ENST00000358273.9 link	c.37G>T	p.Val13Leu	missense_variant	Exon 1 of 58	1	NM_001042492.3	ENSP00000351015.4		P21359-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1387732

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

684784

African (AFR)

AF:

0.00

AC:

AN:

31584

American (AMR)

AF:

0.00

AC:

AN:

35662

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25118

East Asian (EAS)

AF:

0.00

AC:

AN:

35868

South Asian (SAS)

AF:

0.00

AC:

AN:

79142

European-Finnish (FIN)

AF:

0.00

AC:

AN:

39912

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4152

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1078548

Other (OTH)

AF:

0.00

AC:

AN:

57746

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Hereditary cancer-predisposing syndrome;CN230736:Cardiovascular phenotype

Uncertain:1

Feb 22, 2019

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.V13L variant (also known as c.37G>T), located in coding exon 1 of the NF1 gene, results from a G to T substitution at nucleotide position 37. The valine at codon 13 is replaced by leucine, an amino acid with highly similar properties. This nucleotide position is highly conserved in available vertebrate species. This amino acid position is highly 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 this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.79

BayesDel_addAF

Benign

-0.056

BayesDel_noAF

Benign

-0.32

CADD

Uncertain

(source)

DANN

Benign

0.97

DEOGEN2

Benign

0.39

.;T;.;.

Eigen

Benign

-0.38

Eigen_PC

Benign

-0.27

FATHMM_MKL

Benign

0.64

LIST_S2

Uncertain

0.93

D;D;D;D

M_CAP

Pathogenic

0.44

MetaRNN

Benign

0.16

T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.73

N;N;N;N

PhyloP100

3.8

PrimateAI

Pathogenic

0.93

PROVEAN

Benign

0.26

.;N;N;N

REVEL

Benign

0.12

Sift

Benign

1.0

.;T;T;T

Sift4G

Benign

1.0

.;T;T;T

Polyphen

0.71

P;B;B;.

Vest4

0.41, 0.41

MutPred

0.21

Loss of MoRF binding (P = 0.1173);Loss of MoRF binding (P = 0.1173);Loss of MoRF binding (P = 0.1173);Loss of MoRF binding (P = 0.1173);

MVP

0.45

MPC

0.68

ClinPred

0.52

GERP RS

2.7

PromoterAI

0.085

Neutral

(source)

Varity_R

0.12

gMVP

0.77

Mutation Taster

=79/21

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over