Variant 1-107642621-G-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_006113.5(VAV3):c.1912C>G(p.Gln638Glu) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.00000685 in 1,460,364 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/23 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000068 ( 0 hom. )

Consequence

VAV3
NM_006113.5 missense, splice_region

Scores

Splicing: ADA: 0.06256

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.43

Variant links:

Genes affected

VAV3 (HGNC:12659): (vav guanine nucleotide exchange factor 3) This gene is a member of the VAV gene family. The VAV proteins are guanine nucleotide exchange factors (GEFs) for Rho family GTPases that activate pathways leading to actin cytoskeletal rearrangements and transcriptional alterations. This gene product acts as a GEF preferentially for RhoG, RhoA, and to a lesser extent, RAC1, and it associates maximally with the nucleotide-free states of these GTPases. Alternatively spliced transcript variants encoding different isoforms have been described for this gene. [provided by RefSeq, Jul 2008]

VAV3 links:

VAV3 (HGNC:):

VAV3 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.17515582).

BS2

High AC in GnomAdExome4 at 10 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
VAV3	NM_006113.5 linkuse as main transcript	c.1912C>G	p.Gln638Glu	missense_variant, splice_region_variant	20/27	ENST00000370056.9	NP_006104.4	Q9UKW4-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
VAV3	ENST00000370056.9 linkuse as main transcript	c.1912C>G	p.Gln638Glu	missense_variant, splice_region_variant	20/27	1	NM_006113.5	ENSP00000359073.4		Q9UKW4-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000360

AC:

AN:

249770

Hom.:

AF XY:

0.0000148

AC XY:

AN XY:

134992

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000493

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000685

AC:

AN:

1460364

Hom.:

Cov.:

AF XY:

0.00000413

AC XY:

AN XY:

726492

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000253

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Bravo

AF:

0.0000302

ExAC

AF:

0.0000247

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 10, 2023

The c.1912C>G (p.Q638E) alteration is located in exon 20 (coding exon 20) of the VAV3 gene. This alteration results from a C to G substitution at nucleotide position 1912, causing the glutamine (Q) at amino acid position 638 to be replaced by a glutamic acid (E). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.32

BayesDel_noAF

Benign

-0.38

CADD

Uncertain

DANN

Benign

0.94

DEOGEN2

Benign

0.034

T;.;.

Eigen

Benign

0.066

Eigen_PC

Uncertain

0.23

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.88

D;D;D

M_CAP

Benign

0.014

MetaRNN

Benign

0.18

T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.1

L;L;.

PrimateAI

Uncertain

0.58

PROVEAN

Benign

0.43

N;N;N

REVEL

Benign

0.23

Sift

Benign

1.0

T;T;T

Sift4G

Benign

1.0

T;T;T

Polyphen

0.016

B;.;B

Vest4

0.65

MutPred

0.58

Gain of disorder (P = 0.2572);Gain of disorder (P = 0.2572);.;

MVP

0.48

MPC

0.21

ClinPred

0.19

GERP RS

5.4

Varity_R

0.19

gMVP

0.49

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.063

dbscSNV1_RF

Benign

0.41

SpliceAI score (max)

0.14

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