1-107596339-T-C

Position:

• chr1-107596339-T-C

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP7 BA1

The NM_006113.5(VAV3):​c.2223A>G​(p.Glu741Glu) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0566 in 1,610,188 control chromosomes in the GnomAD database, including 2,785 homozygotes. In-silico tool predicts a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.051 (214 hom., cov: 32)
  • Exomes 𝑓: 0.057 (2571 hom.)
• Consequence: VAV3 NM_006113.5 splice_region, synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.03

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]

VAV3 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.48).
• BP7: Synonymous conserved (PhyloP=1.03 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0594 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
VAV3	NM_006113.5	c.2223A>G	p.Glu741Glu	splice_region_variant, synonymous_variant	25/27	ENST00000370056.9	NP_006104.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
VAV3	ENST00000370056.9	c.2223A>G	p.Glu741Glu	splice_region_variant, synonymous_variant	25/27	1	NM_006113.5	ENSP00000359073.4

Frequencies

GnomAD3 genomes AF: 0.0506 AC: 7691 AN: 152080 Hom.: 216 Cov.: 32

Gnomad AFR AF: 0.0416

Gnomad AMI AF: 0.0921

Gnomad AMR AF: 0.0351

Gnomad ASJ AF: 0.0821

Gnomad EAS AF: 0.000769

Gnomad SAS AF: 0.0568

Gnomad FIN AF: 0.0477

Gnomad MID AF: 0.0854

Gnomad NFE AF: 0.0609

Gnomad OTH AF: 0.0526

GnomAD3 exomes AF: 0.0497 AC: 12287 AN: 247272 Hom.: 369 AF XY: 0.0517 AC XY: 6906 AN XY: 133486

Gnomad AFR exome AF: 0.0395

Gnomad AMR exome AF: 0.0229

Gnomad ASJ exome AF: 0.0911

Gnomad EAS exome AF: 0.000219

Gnomad SAS exome AF: 0.0541

Gnomad FIN exome AF: 0.0477

Gnomad NFE exome AF: 0.0625

Gnomad OTH exome AF: 0.0562

GnomAD4 exome AF: 0.0572 AC: 83444 AN: 1457990 Hom.: 2571 Cov.: 31 AF XY: 0.0575 AC XY: 41666 AN XY: 725144

Gnomad4 AFR exome AF: 0.0406

Gnomad4 AMR exome AF: 0.0247

Gnomad4 ASJ exome AF: 0.0921

Gnomad4 EAS exome AF: 0.000202

Gnomad4 SAS exome AF: 0.0546

Gnomad4 FIN exome AF: 0.0446

Gnomad4 NFE exome AF: 0.0611

Gnomad4 OTH exome AF: 0.0541

GnomAD4 genome AF: 0.0506 AC: 7697 AN: 152198 Hom.: 214 Cov.: 32 AF XY: 0.0499 AC XY: 3714 AN XY: 74424

Gnomad4 AFR AF: 0.0417

Gnomad4 AMR AF: 0.0350

Gnomad4 ASJ AF: 0.0821

Gnomad4 EAS AF: 0.000771

Gnomad4 SAS AF: 0.0566

Gnomad4 FIN AF: 0.0477

Gnomad4 NFE AF: 0.0609

Gnomad4 OTH AF: 0.0520

Alfa AF: 0.0602 Hom.: 213

Bravo AF: 0.0489

EpiCase AF: 0.0615

EpiControl AF: 0.0628

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.48
CADD	Benign	9.2
DANN	Benign	0.74

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.14		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: rs17229705; hg19: chr1-108138961;