rs7528153

chr1-107765105-T-A

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_006113.5(VAV3):c.892A>T(p.Thr298Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.656 in 1,611,246 control chromosomes in the GnomAD database, including 355,014 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.63 (31093 hom., cov: 32)
  • Exomes 𝑓: 0.66 (323921 hom.)
• Consequence: VAV3 NM_006113.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.851

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]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=3.0051121E-6).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.696 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
VAV3	NM_006113.5	c.892A>T	p.Thr298Ser	missense_variant	9/27	ENST00000370056.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
VAV3	ENST00000370056.9	c.892A>T	p.Thr298Ser	missense_variant	9/27	1	NM_006113.5	P1

Frequencies

GnomAD3 genomes AF: 0.633 AC: 96056 AN: 151864 Hom.: 31083 Cov.: 32

Gnomad AFR AF: 0.605

Gnomad AMI AF: 0.488

Gnomad AMR AF: 0.532

Gnomad ASJ AF: 0.662

Gnomad EAS AF: 0.395

Gnomad SAS AF: 0.385

Gnomad FIN AF: 0.678

Gnomad MID AF: 0.661

Gnomad NFE AF: 0.701

Gnomad OTH AF: 0.637

GnomAD3 exomes AF: 0.584 AC: 146399 AN: 250758 Hom.: 45528 AF XY: 0.586 AC XY: 79511 AN XY: 135586

Gnomad AFR exome AF: 0.603

Gnomad AMR exome AF: 0.386

Gnomad ASJ exome AF: 0.658

Gnomad EAS exome AF: 0.388

Gnomad SAS exome AF: 0.403

Gnomad FIN exome AF: 0.685

Gnomad NFE exome AF: 0.694

Gnomad OTH exome AF: 0.619

GnomAD4 exome AF: 0.658 AC: 960257 AN: 1459264 Hom.: 323921 Cov.: 35 AF XY: 0.652 AC XY: 473227 AN XY: 726038

Gnomad4 AFR exome AF: 0.602

Gnomad4 AMR exome AF: 0.402

Gnomad4 ASJ exome AF: 0.657

Gnomad4 EAS exome AF: 0.372

Gnomad4 SAS exome AF: 0.407

Gnomad4 FIN exome AF: 0.685

Gnomad4 NFE exome AF: 0.699

Gnomad4 OTH exome AF: 0.646

GnomAD4 genome AF: 0.632 AC: 96106 AN: 151982 Hom.: 31093 Cov.: 32 AF XY: 0.626 AC XY: 46506 AN XY: 74274

Gnomad4 AFR AF: 0.605

Gnomad4 AMR AF: 0.531

Gnomad4 ASJ AF: 0.662

Gnomad4 EAS AF: 0.396

Gnomad4 SAS AF: 0.384

Gnomad4 FIN AF: 0.678

Gnomad4 NFE AF: 0.701

Gnomad4 OTH AF: 0.634

Alfa AF: 0.675 Hom.: 26404

Bravo AF: 0.618

TwinsUK AF: 0.688 AC: 2552

ALSPAC AF: 0.704 AC: 2713

ESP6500AA AF: 0.613 AC: 2699

ESP6500EA AF: 0.696 AC: 5984

ExAC AF: 0.588 AC: 71363

Asia WGS AF: 0.408 AC: 1420 AN: 3478

EpiCase AF: 0.691

EpiControl AF: 0.689

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.083
BayesDel_addAF	Benign	-0.60	T
BayesDel_noAF	Benign	-0.49
Cadd	Benign	21
Dann	Benign	0.92
DEOGEN2	Benign	0.057	T;.
Eigen	Benign	-0.23
Eigen_PC	Benign	-0.073
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.56	T;T
MetaRNN	Benign	0.0000030	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.2	L;L
MutationTaster	Benign	0.00092	P;P;P
PrimateAI	Uncertain	0.63	T
PROVEAN	Benign	-0.16	N;N
REVEL	Benign	0.049
Sift	Benign	0.62	T;T
Sift4G	Benign	0.67	T;T
Polyphen		0.022	B;.
Vest4		0.074
MPC		0.17
ClinPred		0.027	T
GERP RS		4.5
Varity_R		0.051
gMVP		0.11

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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

Other links and lift over

dbSNP: rs7528153; hg19: chr1-108307727; COSMIC: COSV58384420; COSMIC: COSV58384420;