chr1-107642687-G-A

Variant names:

• chr1-107642687-G-A
• rs12410676
• NM_006113.5:c.1846C>T

Variant summary

Our verdict is Benign. The variant received -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. 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 0.11 (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
• Publications: 22 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=0.002140373).
• 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 rank	MANE	Protein	UniProt
VAV3	NM_006113.5	c.1846C>T	p.Pro616Ser	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.1846C>T	p.Pro616Ser	missense_variant	Exon 20 of 27	1	NM_006113.5	ENSP00000359073.4

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

GnomAD2 exomes AF: 0.137 AC: 34379 AN: 250354 AF XY: 0.139

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 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

African (AFR) AF: 0.0606 AC: 2023 AN: 33404

American (AMR) AF: 0.172 AC: 7672 AN: 44584

Ashkenazi Jewish (ASJ) AF: 0.112 AC: 2931 AN: 26102

East Asian (EAS) AF: 0.241 AC: 9545 AN: 39652

South Asian (SAS) AF: 0.199 AC: 17159 AN: 86142

European-Finnish (FIN) AF: 0.0814 AC: 4347 AN: 53408

Middle Eastern (MID) AF: 0.128 AC: 738 AN: 5750

European-Non Finnish (NFE) AF: 0.125 AC: 139280 AN: 1111432

Other (OTH) AF: 0.130 AC: 7826 AN: 60340

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

African (AFR) AF: 0.0621 AC: 2577 AN: 41494

American (AMR) AF: 0.152 AC: 2313 AN: 15244

Ashkenazi Jewish (ASJ) AF: 0.117 AC: 405 AN: 3464

East Asian (EAS) AF: 0.202 AC: 1036 AN: 5138

South Asian (SAS) AF: 0.214 AC: 1025 AN: 4800

European-Finnish (FIN) AF: 0.0771 AC: 817 AN: 10600

Middle Eastern (MID) AF: 0.0884 AC: 26 AN: 294

European-Non Finnish (NFE) AF: 0.121 AC: 8246 AN: 67962

Other (OTH) AF: 0.131 AC: 276 AN: 2110

Alfa AF: 0.124 Hom.: 3517

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;.
PhyloP100		3.1
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
Mutation Taster		=98/2	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: rs12410676; hg19: chr1-108185309; COSMIC: COSV58382496;