1-107642679-C-G

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -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. 14/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• 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
• Publications: 20 publications found

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

Our verdict: Benign. The variant received -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

GnomAD2 exomes AF: 0.155 AC: 38754 AN: 250406 AF XY: 0.156

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 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

African (AFR) AF: 0.0673 AC: 2249 AN: 33406

American (AMR) AF: 0.182 AC: 8109 AN: 44594

Ashkenazi Jewish (ASJ) AF: 0.141 AC: 3669 AN: 26098

East Asian (EAS) AF: 0.259 AC: 10252 AN: 39658

South Asian (SAS) AF: 0.204 AC: 17573 AN: 86170

European-Finnish (FIN) AF: 0.0950 AC: 5075 AN: 53406

Middle Eastern (MID) AF: 0.137 AC: 785 AN: 5750

European-Non Finnish (NFE) AF: 0.151 AC: 167996 AN: 1111426

Other (OTH) AF: 0.151 AC: 9091 AN: 60350

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

African (AFR) AF: 0.0690 AC: 2866 AN: 41512

American (AMR) AF: 0.169 AC: 2572 AN: 15242

Ashkenazi Jewish (ASJ) AF: 0.143 AC: 495 AN: 3472

East Asian (EAS) AF: 0.221 AC: 1135 AN: 5134

South Asian (SAS) AF: 0.218 AC: 1049 AN: 4810

European-Finnish (FIN) AF: 0.0898 AC: 952 AN: 10600

Middle Eastern (MID) AF: 0.0952 AC: 28 AN: 294

European-Non Finnish (NFE) AF: 0.147 AC: 10005 AN: 67944

Other (OTH) AF: 0.144 AC: 304 AN: 2114

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;.
PhyloP100		-0.045
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
Mutation Taster		=99/1	polymorphism (auto)

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

Other links and lift over

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