1-107596232-C-T

Variant names:

• chr1-107596232-C-T
• NM_006113.5:c.2330G>A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_006113.5(VAV3):​c.2330G>A​(p.Gly777Asp) variant causes a missense 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. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: VAV3 NM_006113.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.80

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

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.10078448).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VAV3	NM_006113.5	c.2330G>A	p.Gly777Asp	missense_variant	Exon 25 of 27	ENST00000370056.9	NP_006104.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
VAV3	ENST00000370056.9	c.2330G>A	p.Gly777Asp	missense_variant	Exon 25 of 27	1	NM_006113.5	ENSP00000359073.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Nov 09, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2330G>A (p.G777D) alteration is located in exon 25 (coding exon 25) of the VAV3 gene. This alteration results from a G to A substitution at nucleotide position 2330, causing the glycine (G) at amino acid position 777 to be replaced by an aspartic acid (D). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	18
DANN	Benign	0.85
DEOGEN2	Benign	0.047	T;.;.
Eigen	Benign	-0.51
Eigen_PC	Benign	-0.41
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.82	T;T;T
M_CAP	Benign	0.023	T
MetaRNN	Benign	0.10	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.1	L;L;.
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-0.65	N;N;N
REVEL	Benign	0.023
Sift	Benign	0.30	T;T;T
Sift4G	Benign	0.28	T;T;T
Polyphen		0.044	B;.;P
Vest4		0.21
MutPred		0.28		Loss of methylation at R776 (P = 0.0552);Loss of methylation at R776 (P = 0.0552);.;
MVP		0.55
MPC		0.26
ClinPred		0.15	T
GERP RS		3.3
Varity_R		0.086
gMVP		0.35

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr1-108138854;