1-107964851-A-C

Variant names:

• chr1-107964851-A-C
• rs146244286
• NM_006113.5:c.19T>G

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 1P and 4B. PP3 BS2

The NM_006113.5(VAV3):​c.19T>G​(p.Cys7Gly) variant causes a missense change. The variant allele was found at a frequency of 0.000467 in 1,607,960 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00022 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00049 (1 hom.)
• Consequence: VAV3 NM_006113.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.44
• Publications: 3 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]

VAV3-AS1 (HGNC:40608): (VAV3 antisense RNA 1)

ACMG classification

Our verdict: Likely_benign. The variant received -3 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.78
• BS2: High AC in GnomAd4 at 34 AD gene.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VAV3	NM_006113.5	MANE Select	c.19T>G	p.Cys7Gly	missense	Exon 1 of 27	NP_006104.4
	VAV3-AS1	NR_046653.1		n.62+347A>C		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VAV3	ENST00000370056.9	TSL:1 MANE Select	c.19T>G	p.Cys7Gly	missense	Exon 1 of 27	ENSP00000359073.4	Q9UKW4-1
	VAV3	ENST00000527011.5	TSL:1	c.19T>G	p.Cys7Gly	missense	Exon 1 of 28	ENSP00000432540.1	Q9UKW4-4
	VAV3	ENST00000923907.1		c.19T>G	p.Cys7Gly	missense	Exon 1 of 28	ENSP00000593966.1

Frequencies

GnomAD3 genomes AF: 0.000224 AC: 34 AN: 151958 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000145

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.000578

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000324

Gnomad OTH AF: 0.000479

GnomAD2 exomes AF: 0.000268 AC: 65 AN: 242264 AF XY: 0.000266

Gnomad AFR exome AF: 0.000193

Gnomad AMR exome AF: 0.000153

Gnomad ASJ exome AF: 0.000810

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000420

Gnomad OTH exome AF: 0.000512

GnomAD4 exome AF: 0.000492 AC: 717 AN: 1456002 Hom.: 1 Cov.: 31 AF XY: 0.000492 AC XY: 356 AN XY: 724122

African (AFR) AF: 0.000120 AC: 4 AN: 33324

American (AMR) AF: 0.000204 AC: 9 AN: 44052

Ashkenazi Jewish (ASJ) AF: 0.000808 AC: 21 AN: 26006

East Asian (EAS) AF: 0.00 AC: 0 AN: 39340

South Asian (SAS) AF: 0.00 AC: 0 AN: 85158

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52880

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5706

European-Non Finnish (NFE) AF: 0.000597 AC: 662 AN: 1109378

Other (OTH) AF: 0.000349 AC: 21 AN: 60158

GnomAD4 genome AF: 0.000224 AC: 34 AN: 151958 Hom.: 0 Cov.: 32 AF XY: 0.000216 AC XY: 16 AN XY: 74242

African (AFR) AF: 0.000145 AC: 6 AN: 41408

American (AMR) AF: 0.000196 AC: 3 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.000578 AC: 2 AN: 3460

East Asian (EAS) AF: 0.00 AC: 0 AN: 5168

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10578

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000324 AC: 22 AN: 67936

Other (OTH) AF: 0.000479 AC: 1 AN: 2086

Alfa AF: 0.000443 Hom.: 0

Bravo AF: 0.000317

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00105 AC: 9

ExAC AF: 0.000206 AC: 25

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.67
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Pathogenic	0.24
CADD	Pathogenic	28
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.64	D
Eigen	Uncertain	0.48
Eigen_PC	Uncertain	0.49
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	1.0	D
M_CAP	Pathogenic	0.34	D
MetaRNN	Pathogenic	0.78	D
MetaSVM	Uncertain	-0.17	T
MutationAssessor	Pathogenic	3.1	M
PhyloP100		5.4
PrimateAI	Pathogenic	0.80	D
PROVEAN	Pathogenic	-7.3	D
REVEL	Pathogenic	0.75
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.0090	D
Polyphen		0.99	D
Vest4		0.73
MVP		0.93
MPC		0.84
ClinPred		0.50	D
GERP RS		4.7
PromoterAI		0.035	Neutral
Varity_R		0.85
gMVP		0.84
Mutation Taster		=13/87	disease causing

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: rs146244286; hg19: chr1-108507473;