NM_006113.5:c.1854G>C

Variant names:

• chr1-107642679-C-G
• rs12403266
• NM_006113.5:c.1854G>C

Variant summary

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

The NM_006113.5(VAV3):​c.1854G>C​(p.Gln618His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.151 in 1,612,892 control chromosomes in the GnomAD database, including 19,639 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 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 the same amino acid substitution has been previously reported as Likely benign in UniProt.

• Frequency:
  • Genomes: 𝑓 0.13 (1412 hom., cov: 32)
  • Exomes 𝑓: 0.15 (18227 hom.)
• Consequence: VAV3 NM_006113.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0450

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=0.005578637).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.21 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VAV3	NM_006113.5	c.1854G>C	p.Gln618His	missense_variant	Exon 20 of 27	ENST00000370056.9	NP_006104.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
VAV3	ENST00000370056.9	c.1854G>C	p.Gln618His	missense_variant	Exon 20 of 27	1	NM_006113.5	ENSP00000359073.4

Frequencies

GnomAD3 genomes AF: 0.128 AC: 19516 AN: 151916 Hom.: 1409 Cov.: 32

Gnomad AFR AF: 0.0691

Gnomad AMI AF: 0.139

Gnomad AMR AF: 0.169

Gnomad ASJ AF: 0.143

Gnomad EAS AF: 0.220

Gnomad SAS AF: 0.218

Gnomad FIN AF: 0.0898

Gnomad MID AF: 0.0886

Gnomad NFE AF: 0.147

Gnomad OTH AF: 0.143

GnomAD3 exomes AF: 0.155 AC: 38754 AN: 250406 Hom.: 3339 AF XY: 0.156 AC XY: 21111 AN XY: 135304

Gnomad AFR exome AF: 0.0676

Gnomad AMR exome AF: 0.184

Gnomad ASJ exome AF: 0.143

Gnomad EAS exome AF: 0.226

Gnomad SAS exome AF: 0.202

Gnomad FIN exome AF: 0.0915

Gnomad NFE exome AF: 0.148

Gnomad OTH exome AF: 0.148

GnomAD4 exome AF: 0.154 AC: 224799 AN: 1460858 Hom.: 18227 Cov.: 32 AF XY: 0.155 AC XY: 112533 AN XY: 726712

Gnomad4 AFR exome AF: 0.0673

Gnomad4 AMR exome AF: 0.182

Gnomad4 ASJ exome AF: 0.141

Gnomad4 EAS exome AF: 0.259

Gnomad4 SAS exome AF: 0.204

Gnomad4 FIN exome AF: 0.0950

Gnomad4 NFE exome AF: 0.151

Gnomad4 OTH exome AF: 0.151

GnomAD4 genome AF: 0.128 AC: 19533 AN: 152034 Hom.: 1412 Cov.: 32 AF XY: 0.128 AC XY: 9548 AN XY: 74314

Gnomad4 AFR AF: 0.0690

Gnomad4 AMR AF: 0.169

Gnomad4 ASJ AF: 0.143

Gnomad4 EAS AF: 0.221

Gnomad4 SAS AF: 0.218

Gnomad4 FIN AF: 0.0898

Gnomad4 NFE AF: 0.147

Gnomad4 OTH AF: 0.144

Alfa AF: 0.142 Hom.: 531

Bravo AF: 0.131

TwinsUK AF: 0.163 AC: 604

ALSPAC AF: 0.146 AC: 563

ESP6500AA AF: 0.0781 AC: 344

ESP6500EA AF: 0.150 AC: 1288

ExAC AF: 0.154 AC: 18747

Asia WGS AF: 0.225 AC: 783 AN: 3478

EpiCase AF: 0.150

EpiControl AF: 0.150

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.062
BayesDel_addAF	Benign	-0.75	T
BayesDel_noAF	Benign	-0.70
CADD	Benign	11
DANN	Benign	0.12
DEOGEN2	Benign	0.027	T;.;.
Eigen	Benign	-0.61
Eigen_PC	Benign	-0.61
FATHMM_MKL	Benign	0.085	N
LIST_S2	Benign	0.16	T;T;T
MetaRNN	Benign	0.0056	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.84	N;N;.
PrimateAI	Uncertain	0.62	T
PROVEAN	Benign	0.42	N;N;N
REVEL	Benign	0.018
Sift	Benign	0.078	T;T;T
Sift4G	Benign	0.33	T;T;T
Polyphen		0.0	B;.;B
Vest4		0.11
MutPred		0.19		Loss of disorder (P = 0.1741);Loss of disorder (P = 0.1741);.;
MPC		0.18
ClinPred		0.0017	T
GERP RS		-0.38
Varity_R		0.055
gMVP		0.29

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

LitVar

Other links and lift over

dbSNP: rs12403266; hg19: chr1-108185301; COSMIC: COSV58382481;