19-6833978-G-T

Position:

• chr19-6833978-G-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_005428.4(VAV1):​c.1777+25G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.823 in 1,613,494 control chromosomes in the GnomAD database, including 560,310 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.68 (40367 hom., cov: 29)
  • Exomes 𝑓: 0.84 (519943 hom.)
• Consequence: VAV1 NM_005428.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.728

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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.856 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
VAV1	NM_005428.4	c.1777+25G>T		intron_variant		ENST00000602142.6	NP_005419.2
VAV1	NM_001258206.2	c.1777+25G>T		intron_variant			NP_001245135.1
VAV1	NM_001258207.2	c.1681+25G>T		intron_variant			NP_001245136.1
VAV1	XM_005259642.2	c.1777+25G>T		intron_variant			XP_005259699.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
VAV1	ENST00000602142.6	c.1777+25G>T		intron_variant		1	NM_005428.4	ENSP00000472929.1

Frequencies

GnomAD3 genomes AF: 0.681 AC: 103333 AN: 151792 Hom.: 40365 Cov.: 29

Gnomad AFR AF: 0.267

Gnomad AMI AF: 0.932

Gnomad AMR AF: 0.780

Gnomad ASJ AF: 0.788

Gnomad EAS AF: 0.716

Gnomad SAS AF: 0.855

Gnomad FIN AF: 0.821

Gnomad MID AF: 0.780

Gnomad NFE AF: 0.862

Gnomad OTH AF: 0.721

GnomAD3 exomes AF: 0.793 AC: 199438 AN: 251360 Hom.: 81962 AF XY: 0.806 AC XY: 109567 AN XY: 135862

Gnomad AFR exome AF: 0.254

Gnomad AMR exome AF: 0.795

Gnomad ASJ exome AF: 0.791

Gnomad EAS exome AF: 0.711

Gnomad SAS exome AF: 0.855

Gnomad FIN exome AF: 0.832

Gnomad NFE exome AF: 0.859

Gnomad OTH exome AF: 0.816

GnomAD4 exome AF: 0.838 AC: 1224119 AN: 1461584 Hom.: 519943 Cov.: 50 AF XY: 0.840 AC XY: 610523 AN XY: 727096

Gnomad4 AFR exome AF: 0.247

Gnomad4 AMR exome AF: 0.793

Gnomad4 ASJ exome AF: 0.788

Gnomad4 EAS exome AF: 0.692

Gnomad4 SAS exome AF: 0.853

Gnomad4 FIN exome AF: 0.833

Gnomad4 NFE exome AF: 0.865

Gnomad4 OTH exome AF: 0.805

GnomAD4 genome AF: 0.680 AC: 103348 AN: 151910 Hom.: 40367 Cov.: 29 AF XY: 0.683 AC XY: 50706 AN XY: 74268

Gnomad4 AFR AF: 0.267

Gnomad4 AMR AF: 0.779

Gnomad4 ASJ AF: 0.788

Gnomad4 EAS AF: 0.716

Gnomad4 SAS AF: 0.855

Gnomad4 FIN AF: 0.821

Gnomad4 NFE AF: 0.862

Gnomad4 OTH AF: 0.719

Alfa AF: 0.775 Hom.: 8994

Bravo AF: 0.656

Asia WGS AF: 0.767 AC: 2668 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	3.5
DANN	Benign	0.78

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: rs308199; hg19: chr19-6833989; COSMIC: COSV58378434; COSMIC: COSV58378434;