rs347033

chr19-6822208-T-C

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.450-13T>C variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.2 in 1,566,556 control chromosomes in the GnomAD database, including 32,364 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.22 (3752 hom., cov: 32)
  • Exomes 𝑓: 0.20 (28612 hom.)
• Consequence: VAV1 NM_005428.4 splice_polypyrimidine_tract, intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -2.58

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=-0.88).
• BP6: Variant 19-6822208-T-C is Benign according to our data. Variant chr19-6822208-T-C is described in ClinVar as [Benign]. Clinvar id is 403602.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.276 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
VAV1	NM_005428.4	c.450-13T>C		splice_polypyrimidine_tract_variant, intron_variant		ENST00000602142.6
VAV1	NM_001258206.2	c.450-13T>C		splice_polypyrimidine_tract_variant, intron_variant
VAV1	NM_001258207.2	c.450-13T>C		splice_polypyrimidine_tract_variant, intron_variant
VAV1	XM_005259642.2	c.450-13T>C		splice_polypyrimidine_tract_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
VAV1	ENST00000602142.6	c.450-13T>C		splice_polypyrimidine_tract_variant, intron_variant		1	NM_005428.4	P1

Frequencies

GnomAD3 genomes AF: 0.216 AC: 32839 AN: 151896 Hom.: 3737 Cov.: 32

Gnomad AFR AF: 0.280

Gnomad AMI AF: 0.305

Gnomad AMR AF: 0.162

Gnomad ASJ AF: 0.185

Gnomad EAS AF: 0.238

Gnomad SAS AF: 0.156

Gnomad FIN AF: 0.202

Gnomad MID AF: 0.206

Gnomad NFE AF: 0.195

Gnomad OTH AF: 0.223

GnomAD3 exomes AF: 0.190 AC: 34138 AN: 179804 Hom.: 3432 AF XY: 0.188 AC XY: 17838 AN XY: 94896

Gnomad AFR exome AF: 0.289

Gnomad AMR exome AF: 0.137

Gnomad ASJ exome AF: 0.195

Gnomad EAS exome AF: 0.227

Gnomad SAS exome AF: 0.156

Gnomad FIN exome AF: 0.199

Gnomad NFE exome AF: 0.195

Gnomad OTH exome AF: 0.178

GnomAD4 exome AF: 0.199 AC: 281148 AN: 1414542 Hom.: 28612 Cov.: 34 AF XY: 0.198 AC XY: 138135 AN XY: 698928

Gnomad4 AFR exome AF: 0.285

Gnomad4 AMR exome AF: 0.139

Gnomad4 ASJ exome AF: 0.192

Gnomad4 EAS exome AF: 0.209

Gnomad4 SAS exome AF: 0.161

Gnomad4 FIN exome AF: 0.195

Gnomad4 NFE exome AF: 0.201

Gnomad4 OTH exome AF: 0.199

GnomAD4 genome AF: 0.216 AC: 32884 AN: 152014 Hom.: 3752 Cov.: 32 AF XY: 0.215 AC XY: 15949 AN XY: 74320

Gnomad4 AFR AF: 0.280

Gnomad4 AMR AF: 0.162

Gnomad4 ASJ AF: 0.185

Gnomad4 EAS AF: 0.238

Gnomad4 SAS AF: 0.156

Gnomad4 FIN AF: 0.202

Gnomad4 NFE AF: 0.195

Gnomad4 OTH AF: 0.224

Alfa AF: 0.196 Hom.: 6184

Bravo AF: 0.218

Asia WGS AF: 0.196 AC: 684 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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 -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
Cadd	Benign	4.4
Dann	Benign	0.32

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: rs347033; hg19: chr19-6822219; COSMIC: COSV58393278; COSMIC: COSV58393278;