rs28617395

Positions:

• chr19-6821614-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_005428.4(VAV1):​c.322-8C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.149 in 1,613,840 control chromosomes in the GnomAD database, including 19,113 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.13 (1412 hom., cov: 32)
  • Exomes 𝑓: 0.15 (17701 hom.)
• Consequence: VAV1 NM_005428.4 splice_region, intron
• Scores: Splicing: ADA: 0.00003354
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -1.80

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 19-6821614-C-T is Benign according to our data. Variant chr19-6821614-C-T is described in ClinVar as [Benign]. Clinvar id is 403601.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.156 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
VAV1	NM_005428.4	c.322-8C>T		splice_region_variant, intron_variant		ENST00000602142.6	NP_005419.2
VAV1	NM_001258206.2	c.322-8C>T		splice_region_variant, intron_variant			NP_001245135.1
VAV1	NM_001258207.2	c.322-8C>T		splice_region_variant, intron_variant			NP_001245136.1
VAV1	XM_005259642.2	c.322-8C>T		splice_region_variant, intron_variant			XP_005259699.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
VAV1	ENST00000602142.6	c.322-8C>T		splice_region_variant, intron_variant		1	NM_005428.4	ENSP00000472929.1

Frequencies

GnomAD3 genomes AF: 0.128 AC: 19485 AN: 152018 Hom.: 1404 Cov.: 32

Gnomad AFR AF: 0.101

Gnomad AMI AF: 0.181

Gnomad AMR AF: 0.0957

Gnomad ASJ AF: 0.141

Gnomad EAS AF: 0.0440

Gnomad SAS AF: 0.100

Gnomad FIN AF: 0.128

Gnomad MID AF: 0.161

Gnomad NFE AF: 0.159

Gnomad OTH AF: 0.139

GnomAD3 exomes AF: 0.125 AC: 31453 AN: 251296 Hom.: 2251 AF XY: 0.128 AC XY: 17423 AN XY: 135826

Gnomad AFR exome AF: 0.103

Gnomad AMR exome AF: 0.0696

Gnomad ASJ exome AF: 0.150

Gnomad EAS exome AF: 0.0434

Gnomad SAS exome AF: 0.109

Gnomad FIN exome AF: 0.126

Gnomad NFE exome AF: 0.160

Gnomad OTH exome AF: 0.129

GnomAD4 exome AF: 0.151 AC: 221210 AN: 1461706 Hom.: 17701 Cov.: 35 AF XY: 0.151 AC XY: 109542 AN XY: 727154

Gnomad4 AFR exome AF: 0.0959

Gnomad4 AMR exome AF: 0.0732

Gnomad4 ASJ exome AF: 0.148

Gnomad4 EAS exome AF: 0.0426

Gnomad4 SAS exome AF: 0.112

Gnomad4 FIN exome AF: 0.123

Gnomad4 NFE exome AF: 0.165

Gnomad4 OTH exome AF: 0.143

GnomAD4 genome AF: 0.128 AC: 19510 AN: 152134 Hom.: 1412 Cov.: 32 AF XY: 0.125 AC XY: 9281 AN XY: 74364

Gnomad4 AFR AF: 0.101

Gnomad4 AMR AF: 0.0954

Gnomad4 ASJ AF: 0.141

Gnomad4 EAS AF: 0.0441

Gnomad4 SAS AF: 0.0997

Gnomad4 FIN AF: 0.128

Gnomad4 NFE AF: 0.159

Gnomad4 OTH AF: 0.141

Alfa AF: 0.146 Hom.: 1072

Bravo AF: 0.127

Asia WGS AF: 0.0920 AC: 321 AN: 3478

EpiCase AF: 0.162

EpiControl AF: 0.175

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

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	-	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 28, 2023	- -

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 21, 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	-0.86
CADD	Benign	0.11
DANN	Benign	0.48

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000034
dbscSNV1_RF	Benign	0.0
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: rs28617395; hg19: chr19-6821625;