rs17229705

Positions:

• chr1-107596339-T-A
• chr1-107596339-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM2 PM5 BP4

The NM_006113.5(VAV3):​c.2223A>T​(p.Glu741Asp) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict 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. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E741G) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: VAV3 NM_006113.5 missense, splice_region
• 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 Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr1-107596340-T-C is described in Lovd as [Likely_pathogenic].
• BP4: Computational evidence support a benign effect (MetaRNN=0.36765683).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
VAV3	NM_006113.5	c.2223A>T	p.Glu741Asp	missense_variant, splice_region_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>T	p.Glu741Asp	missense_variant, splice_region_variant	25/27	1	NM_006113.5	ENSP00000359073.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.24
BayesDel_addAF	Benign	-0.00095	T
BayesDel_noAF	Benign	-0.24
CADD	Benign	15
DANN	Uncertain	0.98
DEOGEN2	Benign	0.37	T;.;.
Eigen	Benign	-0.58
Eigen_PC	Benign	-0.41
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Uncertain	0.88	D;D;D
M_CAP	Benign	0.058	D
MetaRNN	Benign	0.37	T;T;T
MetaSVM	Benign	-0.57	T
MutationAssessor	Benign	0.010	N;N;.
PrimateAI	Pathogenic	0.82	D
PROVEAN	Benign	-1.5	N;N;N
REVEL	Benign	0.056
Sift	Benign	0.093	T;T;T
Sift4G	Benign	0.22	T;T;T
Polyphen		0.0010	B;.;B
Vest4		0.28
MutPred		0.65		Loss of loop (P = 0.1242);Loss of loop (P = 0.1242);.;
MVP		0.81
MPC		0.17
ClinPred		0.27	T
GERP RS		1.9
Varity_R		0.17
gMVP		0.55

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: rs17229705; hg19: chr1-108138961;