rs201002344

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 1P and 6B. PP2BP4_ModerateBS2

The NM_005428.4(VAV1):c.650A>G(p.Gln217Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000897 in 1,548,110 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q217K) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00047 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00094 ( 1 hom. )

Consequence

VAV1
NM_005428.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:3

Conservation

PhyloP100: 1.68

Variant links:

Genes affected

VAV1 (HGNC:12657): (vav guanine nucleotide exchange factor 1) 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. The encoded protein is important in hematopoiesis, playing a role in T-cell and B-cell development and activation. The encoded protein has been identified as the specific binding partner of Nef proteins from HIV-1. Coexpression and binding of these partners initiates profound morphological changes, cytoskeletal rearrangements and the JNK/SAPK signaling cascade, leading to increased levels of viral transcription and replication. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene. [provided by RefSeq, Apr 2012]

VAV1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -5 ACMG points.

PP2

Missense variant where missense usually causes diseases, VAV1

BP4

Computational evidence support a benign effect (MetaRNN=0.11311263).

BS2

High AC in GnomAd at 71 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
VAV1	NM_005428.4 linkuse as main transcript	c.650A>G	p.Gln217Arg	missense_variant	6/27	ENST00000602142.6
VAV1	NM_001258206.2 linkuse as main transcript	c.650A>G	p.Gln217Arg	missense_variant	6/26
VAV1	XM_005259642.2 linkuse as main transcript	c.650A>G	p.Gln217Arg	missense_variant	6/26
VAV1	NM_001258207.2 linkuse as main transcript	c.558+181A>G		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
VAV1	ENST00000602142.6 linkuse as main transcript	c.650A>G	p.Gln217Arg	missense_variant	6/27	1	NM_005428.4	P1	P15498-1

Frequencies

GnomAD3 genomes

AF:

0.000467

AC:

AN:

152156

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000169

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:

0.000941

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000323

AC:

AN:

151726

Hom.:

AF XY:

0.000322

AC XY:

AN XY:

80822

show subpopulations

Gnomad AFR exome

AF:

0.000118

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:

0.000802

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000944

AC:

1318

AN:

1395836

Hom.:

Cov.:

AF XY:

0.000891

AC XY:

614

AN XY:

688950

show subpopulations

Gnomad4 AFR exome

AF:

0.000190

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:

0.0000220

Gnomad4 NFE exome

AF:

0.00117

Gnomad4 OTH exome

AF:

0.000898

GnomAD4 genome

AF:

0.000466

AC:

AN:

152274

Hom.:

Cov.:

AF XY:

0.000349

AC XY:

AN XY:

74458

show subpopulations

Gnomad4 AFR

AF:

0.000168

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:

0.000941

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000603

Hom.:

Bravo

AF:

0.000457

TwinsUK

AF:

0.000809

AC:

ALSPAC

AF:

0.000778

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000477

AC:

ExAC

AF:

0.000122

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Jan 16, 2024	This sequence change replaces glutamine, which is neutral and polar, with arginine, which is basic and polar, at codon 217 of the VAV1 protein (p.Gln217Arg). This variant is present in population databases (rs201002344, gnomAD 0.07%), and has an allele count higher than expected for a pathogenic variant. This variant has not been reported in the literature in individuals affected with VAV1-related conditions. ClinVar contains an entry for this variant (Variation ID: 548023). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant¬†is likely to be tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Jan 29, 2018	- -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 13, 2021

The c.650A>G (p.Q217R) alteration is located in exon 6 (coding exon 6) of the VAV1 gene. This alteration results from a A to G substitution at nucleotide position 650, causing the glutamine (Q) at amino acid position 217 to be replaced by an arginine (R). 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

0.098

BayesDel_addAF

Benign

-0.35

BayesDel_noAF

Benign

-0.37

Cadd

Benign

Dann

Uncertain

0.98

Eigen

Benign

-0.23

Eigen_PC

Benign

-0.094

FATHMM_MKL

Benign

0.68

LIST_S2

Uncertain

0.90

D;D;D;D

M_CAP

Benign

0.046

MetaRNN

Benign

0.11

T;T;T;T

MetaSVM

Benign

-0.97

MutationTaster

Benign

0.99

D;D

PROVEAN

Benign

-1.3

N;.;.;.

REVEL

Benign

0.15

Sift

Benign

0.21

T;.;.;.

Sift4G

Benign

0.13

T;T;T;T

Polyphen

0.067, 0.025

.;B;B;.

Vest4

0.34

MVP

0.73

MPC

1.1

ClinPred

0.047

GERP RS

4.3

Varity_R

0.34

gMVP

0.34

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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