chr1-107596339-T-A

Variant names:

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

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 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. 14/22 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.

• Frequency: Genomes: not found (cov: 32)
• Consequence: VAV3 NM_006113.5 missense, splice_region
• 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: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.36765683).

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>T	p.Glu741Asp	missense splice_region	Exon 25 of 27	NP_006104.4
	VAV3	NM_001079874.2		c.543A>T	p.Glu181Asp	missense splice_region	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>T	p.Glu741Asp	missense splice_region	Exon 25 of 27	ENSP00000359073.4
	VAV3	ENST00000527011.5	TSL:1	c.2223A>T	p.Glu741Asp	missense splice_region	Exon 25 of 28	ENSP00000432540.1
	VAV3	ENST00000415432.6	TSL:1	c.543A>T	p.Glu181Asp	missense splice_region	Exon 8 of 10	ENSP00000394897.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

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
M_CAP	Benign	0.058	D
MetaRNN	Benign	0.37	T
MetaSVM	Benign	-0.57	T
MutationAssessor	Benign	0.010	N
PhyloP100		1.0
PrimateAI	Pathogenic	0.82	D
PROVEAN	Benign	-1.5	N
REVEL	Benign	0.056
Sift	Benign	0.093	T
Sift4G	Benign	0.22	T
Polyphen		0.0010	B
Vest4		0.28
MutPred		0.65		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
Mutation Taster		=78/22	polymorphism

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: rs17229705; hg19: chr1-108138961;