rs12410676

Positions:

• chr1-107642687-G-A

Variant summary

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

The NM_006113.5(VAV3):​c.1846C>T​(p.Pro616Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.129 in 1,612,830 control chromosomes in the GnomAD database, including 14,511 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 same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.11 (1064 hom., cov: 32)
  • Exomes 𝑓: 0.13 (13447 hom.)
• Consequence: VAV3 NM_006113.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.08

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=0.002140373).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.203 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
VAV3	NM_006113.5	c.1846C>T	p.Pro616Ser	missense_variant	20/27	ENST00000370056.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
VAV3	ENST00000370056.9	c.1846C>T	p.Pro616Ser	missense_variant	20/27	1	NM_006113.5	P1

Frequencies

GnomAD3 genomes AF: 0.111 AC: 16828 AN: 151900 Hom.: 1062 Cov.: 32

Gnomad AFR AF: 0.0622

Gnomad AMI AF: 0.136

Gnomad AMR AF: 0.151

Gnomad ASJ AF: 0.117

Gnomad EAS AF: 0.201

Gnomad SAS AF: 0.214

Gnomad FIN AF: 0.0771

Gnomad MID AF: 0.0791

Gnomad NFE AF: 0.121

Gnomad OTH AF: 0.130

GnomAD3 exomes AF: 0.137 AC: 34379 AN: 250354 Hom.: 2715 AF XY: 0.139 AC XY: 18796 AN XY: 135278

Gnomad AFR exome AF: 0.0610

Gnomad AMR exome AF: 0.174

Gnomad ASJ exome AF: 0.114

Gnomad EAS exome AF: 0.206

Gnomad SAS exome AF: 0.197

Gnomad FIN exome AF: 0.0794

Gnomad NFE exome AF: 0.123

Gnomad OTH exome AF: 0.133

GnomAD4 exome AF: 0.131 AC: 191521 AN: 1460814 Hom.: 13447 Cov.: 32 AF XY: 0.133 AC XY: 96355 AN XY: 726698

Gnomad4 AFR exome AF: 0.0606

Gnomad4 AMR exome AF: 0.172

Gnomad4 ASJ exome AF: 0.112

Gnomad4 EAS exome AF: 0.241

Gnomad4 SAS exome AF: 0.199

Gnomad4 FIN exome AF: 0.0814

Gnomad4 NFE exome AF: 0.125

Gnomad4 OTH exome AF: 0.130

GnomAD4 genome AF: 0.111 AC: 16845 AN: 152016 Hom.: 1064 Cov.: 32 AF XY: 0.112 AC XY: 8304 AN XY: 74316

Gnomad4 AFR AF: 0.0621

Gnomad4 AMR AF: 0.152

Gnomad4 ASJ AF: 0.117

Gnomad4 EAS AF: 0.202

Gnomad4 SAS AF: 0.214

Gnomad4 FIN AF: 0.0771

Gnomad4 NFE AF: 0.121

Gnomad4 OTH AF: 0.131

Alfa AF: 0.125 Hom.: 2846

Bravo AF: 0.114

TwinsUK AF: 0.131 AC: 487

ALSPAC AF: 0.122 AC: 469

ESP6500AA AF: 0.0679 AC: 299

ESP6500EA AF: 0.124 AC: 1069

ExAC AF: 0.136 AC: 16516

Asia WGS AF: 0.211 AC: 736 AN: 3478

EpiCase AF: 0.127

EpiControl AF: 0.130

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.67	T
BayesDel_noAF	Benign	-0.59
CADD	Benign	21
DANN	Benign	0.20
DEOGEN2	Benign	0.085	T;.;.
Eigen	Benign	-0.59
Eigen_PC	Benign	-0.50
FATHMM_MKL	Uncertain	0.80	D
LIST_S2	Benign	0.57	T;T;T
MetaRNN	Benign	0.0021	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.5	L;L;.
MutationTaster	Benign	0.10	P;P;P;P
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	-1.3	N;N;N
REVEL	Benign	0.048
Sift	Benign	0.48	T;T;T
Sift4G	Benign	0.27	T;T;T
Polyphen		0.018	B;.;B
Vest4		0.20
MPC		0.20
ClinPred		0.0035	T
GERP RS		3.8
Varity_R		0.034
gMVP		0.33

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: rs12410676; hg19: chr1-108185309; COSMIC: COSV58382496;