19-6833978-G-T

Variant names:

• chr19-6833978-G-T
• rs308199
• NM_005428.4:c.1777+25G>T

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 10 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 -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 rank	MANE	Protein	UniProt
VAV1	NM_005428.4	c.1777+25G>T		intron_variant	Intron 19 of 26	ENST00000602142.6	NP_005419.2
VAV1	NM_001258206.2	c.1777+25G>T		intron_variant	Intron 19 of 25		NP_001245135.1
VAV1	NM_001258207.2	c.1681+25G>T		intron_variant	Intron 18 of 25		NP_001245136.1
VAV1	XM_005259642.2	c.1777+25G>T		intron_variant	Intron 19 of 25		XP_005259699.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
VAV1	ENST00000602142.6	c.1777+25G>T		intron_variant	Intron 19 of 26	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

GnomAD2 exomes AF: 0.793 AC: 199438 AN: 251360 AF XY: 0.806

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 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

African (AFR) AF: 0.247 AC: 8278 AN: 33472

American (AMR) AF: 0.793 AC: 35449 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.788 AC: 20581 AN: 26132

East Asian (EAS) AF: 0.692 AC: 27470 AN: 39694

South Asian (SAS) AF: 0.853 AC: 73536 AN: 86240

European-Finnish (FIN) AF: 0.833 AC: 44453 AN: 53386

Middle Eastern (MID) AF: 0.766 AC: 4395 AN: 5738

European-Non Finnish (NFE) AF: 0.865 AC: 961384 AN: 1111836

Other (OTH) AF: 0.805 AC: 48573 AN: 60370

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

African (AFR) AF: 0.267 AC: 11057 AN: 41392

American (AMR) AF: 0.779 AC: 11895 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.788 AC: 2733 AN: 3468

East Asian (EAS) AF: 0.716 AC: 3679 AN: 5136

South Asian (SAS) AF: 0.855 AC: 4111 AN: 4806

European-Finnish (FIN) AF: 0.821 AC: 8674 AN: 10566

Middle Eastern (MID) AF: 0.791 AC: 231 AN: 292

European-Non Finnish (NFE) AF: 0.862 AC: 58601 AN: 67964

Other (OTH) AF: 0.719 AC: 1517 AN: 2110

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
PhyloP100		0.73
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: rs308199; hg19: chr19-6833989; COSMIC: COSV58378434; COSMIC: COSV58378434;