19-6772861-G-C

Position:

• chr19-6772861-G-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The ENST00000602142.6(VAV1):​c.54G>C​(p.Pro18=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.125 in 1,613,996 control chromosomes in the GnomAD database, including 13,901 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. P18P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.10 (939 hom., cov: 32)
  • Exomes 𝑓: 0.13 (12962 hom.)
• Consequence: VAV1 ENST00000602142.6 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -1.52

Genes affected

VAV1 (HGNC:12657): (vav guanine nucleotide exchange factor 1) 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. The encoded protein is important in hematopoiesis, playing a role in T-cell and B-cell development and activation. The encoded protein has been identified as the specific binding partner of Nef proteins from HIV-1. Coexpression and binding of these partners initiates profound morphological changes, cytoskeletal rearrangements and the JNK/SAPK signaling cascade, leading to increased levels of viral transcription and replication. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene. [provided by RefSeq, Apr 2012]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.58).
• BP6: Variant 19-6772861-G-C is Benign according to our data. Variant chr19-6772861-G-C is described in ClinVar as [Benign]. Clinvar id is 403600.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.52 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.189 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
VAV1	NM_005428.4	c.54G>C	p.Pro18=	synonymous_variant	1/27	ENST00000602142.6	NP_005419.2
VAV1	NM_001258206.2	c.54G>C	p.Pro18=	synonymous_variant	1/26		NP_001245135.1
VAV1	NM_001258207.2	c.54G>C	p.Pro18=	synonymous_variant	1/26		NP_001245136.1
VAV1	XM_005259642.2	c.54G>C	p.Pro18=	synonymous_variant	1/26		XP_005259699.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
VAV1	ENST00000602142.6	c.54G>C	p.Pro18=	synonymous_variant	1/27	1	NM_005428.4	ENSP00000472929	P1
VAV1	ENST00000304076.6	c.54G>C	p.Pro18=	synonymous_variant	1/26	1		ENSP00000302269
VAV1	ENST00000596764.5	c.54G>C	p.Pro18=	synonymous_variant	1/26	2		ENSP00000469450

Frequencies

GnomAD3 genomes AF: 0.104 AC: 15888 AN: 152112 Hom.: 945 Cov.: 32

Gnomad AFR AF: 0.0715

Gnomad AMI AF: 0.173

Gnomad AMR AF: 0.0860

Gnomad ASJ AF: 0.118

Gnomad EAS AF: 0.00366

Gnomad SAS AF: 0.200

Gnomad FIN AF: 0.109

Gnomad MID AF: 0.177

Gnomad NFE AF: 0.127

Gnomad OTH AF: 0.119

GnomAD3 exomes AF: 0.113 AC: 28281 AN: 250722 Hom.: 2022 AF XY: 0.121 AC XY: 16373 AN XY: 135616

Gnomad AFR exome AF: 0.0714

Gnomad AMR exome AF: 0.0577

Gnomad ASJ exome AF: 0.120

Gnomad EAS exome AF: 0.00441

Gnomad SAS exome AF: 0.209

Gnomad FIN exome AF: 0.111

Gnomad NFE exome AF: 0.126

Gnomad OTH exome AF: 0.119

GnomAD4 exome AF: 0.127 AC: 185779 AN: 1461766 Hom.: 12962 Cov.: 34 AF XY: 0.130 AC XY: 94540 AN XY: 727202

Gnomad4 AFR exome AF: 0.0708

Gnomad4 AMR exome AF: 0.0611

Gnomad4 ASJ exome AF: 0.116

Gnomad4 EAS exome AF: 0.00295

Gnomad4 SAS exome AF: 0.203

Gnomad4 FIN exome AF: 0.108

Gnomad4 NFE exome AF: 0.131

Gnomad4 OTH exome AF: 0.122

GnomAD4 genome AF: 0.104 AC: 15877 AN: 152230 Hom.: 939 Cov.: 32 AF XY: 0.102 AC XY: 7614 AN XY: 74428

Gnomad4 AFR AF: 0.0713

Gnomad4 AMR AF: 0.0856

Gnomad4 ASJ AF: 0.118

Gnomad4 EAS AF: 0.00348

Gnomad4 SAS AF: 0.199

Gnomad4 FIN AF: 0.109

Gnomad4 NFE AF: 0.127

Gnomad4 OTH AF: 0.117

Alfa AF: 0.0619 Hom.: 80

Bravo AF: 0.0991

Asia WGS AF: 0.107 AC: 372 AN: 3478

EpiCase AF: 0.133

EpiControl AF: 0.136

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Mar 29, 2016

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency -

VAV1-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

May 08, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.58
CADD	Benign	7.4
DANN	Benign	0.82

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: rs45448796; hg19: chr19-6772872;