NM_006113.5:c.2223A>G

Variant names:

• chr1-107596339-T-C
• rs17229705
• NM_006113.5:c.2223A>G

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 9 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 -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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006113.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VAV3	NM_006113.5	MANE Select	c.2223A>G	p.Glu741Glu	splice_region synonymous	Exon 25 of 27	NP_006104.4
	VAV3	NM_001079874.2		c.543A>G	p.Glu181Glu	splice_region synonymous	Exon 8 of 10	NP_001073343.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VAV3	ENST00000370056.9	TSL:1 MANE Select	c.2223A>G	p.Glu741Glu	splice_region synonymous	Exon 25 of 27	ENSP00000359073.4
	VAV3	ENST00000527011.5	TSL:1	c.2223A>G	p.Glu741Glu	splice_region synonymous	Exon 25 of 28	ENSP00000432540.1
	VAV3	ENST00000415432.6	TSL:1	c.543A>G	p.Glu181Glu	splice_region synonymous	Exon 8 of 10	ENSP00000394897.2

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

GnomAD2 exomes AF: 0.0497 AC: 12287 AN: 247272 AF XY: 0.0517

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 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

African (AFR) AF: 0.0406 AC: 1351 AN: 33284

American (AMR) AF: 0.0247 AC: 1086 AN: 44038

Ashkenazi Jewish (ASJ) AF: 0.0921 AC: 2387 AN: 25930

East Asian (EAS) AF: 0.000202 AC: 8 AN: 39646

South Asian (SAS) AF: 0.0546 AC: 4659 AN: 85348

European-Finnish (FIN) AF: 0.0446 AC: 2383 AN: 53382

Middle Eastern (MID) AF: 0.0908 AC: 523 AN: 5758

European-Non Finnish (NFE) AF: 0.0611 AC: 67791 AN: 1110382

Other (OTH) AF: 0.0541 AC: 3256 AN: 60222

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

African (AFR) AF: 0.0417 AC: 1734 AN: 41558

American (AMR) AF: 0.0350 AC: 535 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.0821 AC: 285 AN: 3470

East Asian (EAS) AF: 0.000771 AC: 4 AN: 5190

South Asian (SAS) AF: 0.0566 AC: 273 AN: 4822

European-Finnish (FIN) AF: 0.0477 AC: 505 AN: 10598

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

European-Non Finnish (NFE) AF: 0.0609 AC: 4141 AN: 67970

Other (OTH) AF: 0.0520 AC: 110 AN: 2114

Alfa AF: 0.0597 Hom.: 320

Bravo AF: 0.0489

EpiCase AF: 0.0615

EpiControl AF: 0.0628

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.48
CADD	Benign	9.2
DANN	Benign	0.74
PhyloP100		1.0
Mutation Taster		=94/6	polymorphism (auto)

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

Other links and lift over

dbSNP: rs17229705; hg19: chr1-108138961;