19-6772861-G-C

Variant names:

• chr19-6772861-G-C
• rs45448796
• NM_005428.4:c.54G>C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_005428.4(VAV1):​c.54G>C​(p.Pro18Pro) 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 NM_005428.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -1.52
• Publications: 6 publications found

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

Our verdict: Benign. The variant received -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 VariationId 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 rank	MANE	Protein	UniProt
VAV1	NM_005428.4	c.54G>C	p.Pro18Pro	synonymous_variant	Exon 1 of 27	ENST00000602142.6	NP_005419.2
VAV1	NM_001258206.2	c.54G>C	p.Pro18Pro	synonymous_variant	Exon 1 of 26		NP_001245135.1
VAV1	NM_001258207.2	c.54G>C	p.Pro18Pro	synonymous_variant	Exon 1 of 26		NP_001245136.1
VAV1	XM_005259642.2	c.54G>C	p.Pro18Pro	synonymous_variant	Exon 1 of 26		XP_005259699.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
VAV1	ENST00000602142.6	c.54G>C	p.Pro18Pro	synonymous_variant	Exon 1 of 27	1	NM_005428.4	ENSP00000472929.1
VAV1	ENST00000304076.6	c.54G>C	p.Pro18Pro	synonymous_variant	Exon 1 of 26	1		ENSP00000302269.2
VAV1	ENST00000596764.5	c.54G>C	p.Pro18Pro	synonymous_variant	Exon 1 of 26	2		ENSP00000469450.1

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

GnomAD2 exomes AF: 0.113 AC: 28281 AN: 250722 AF XY: 0.121

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 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

African (AFR) AF: 0.0708 AC: 2371 AN: 33478

American (AMR) AF: 0.0611 AC: 2732 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.116 AC: 3025 AN: 26116

East Asian (EAS) AF: 0.00295 AC: 117 AN: 39700

South Asian (SAS) AF: 0.203 AC: 17478 AN: 86252

European-Finnish (FIN) AF: 0.108 AC: 5762 AN: 53410

Middle Eastern (MID) AF: 0.185 AC: 1068 AN: 5764

European-Non Finnish (NFE) AF: 0.131 AC: 145880 AN: 1111948

Other (OTH) AF: 0.122 AC: 7346 AN: 60382

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

African (AFR) AF: 0.0713 AC: 2962 AN: 41542

American (AMR) AF: 0.0856 AC: 1310 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.118 AC: 410 AN: 3470

East Asian (EAS) AF: 0.00348 AC: 18 AN: 5178

South Asian (SAS) AF: 0.199 AC: 962 AN: 4828

European-Finnish (FIN) AF: 0.109 AC: 1152 AN: 10612

Middle Eastern (MID) AF: 0.170 AC: 50 AN: 294

European-Non Finnish (NFE) AF: 0.127 AC: 8608 AN: 67988

Other (OTH) AF: 0.117 AC: 248 AN: 2112

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

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

not specified Benign:1

Mar 29, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

May 08, 2019

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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
PhyloP100		-1.5
PromoterAI		0.075	Neutral
Mutation Taster		=100/0	polymorphism (auto)

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: rs45448796; hg19: chr19-6772872;