19-6799666-T-C

Variant names:

• chr19-6799666-T-C
• rs2546133
• NM_005428.4:c.205-21036T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_005428.4(VAV1):​c.205-21036T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.937 in 151,858 control chromosomes in the GnomAD database, including 66,800 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 0.94 (66800 hom., cov: 28)
• Consequence: VAV1 NM_005428.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -3.42
• Publications: 9 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=-1.03).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.977 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005428.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VAV1	NM_005428.4	MANE Select	c.205-21036T>C		intron	N/A	NP_005419.2
	VAV1	NM_001258206.2		c.205-21036T>C		intron	N/A	NP_001245135.1
	VAV1	NM_001258207.2		c.205-21036T>C		intron	N/A	NP_001245136.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VAV1	ENST00000602142.6	TSL:1 MANE Select	c.205-21036T>C		intron	N/A	ENSP00000472929.1
	VAV1	ENST00000304076.6	TSL:1	c.205-21036T>C		intron	N/A	ENSP00000302269.2
	VAV1	ENST00000599806.5	TSL:1	c.39+15425T>C		intron	N/A	ENSP00000472803.1

Frequencies

GnomAD3 genomes AF: 0.937 AC: 142225 AN: 151740 Hom.: 66752 Cov.: 28

Gnomad AFR AF: 0.982

Gnomad AMI AF: 0.853

Gnomad AMR AF: 0.940

Gnomad ASJ AF: 0.899

Gnomad EAS AF: 1.00

Gnomad SAS AF: 0.923

Gnomad FIN AF: 0.942

Gnomad MID AF: 0.905

Gnomad NFE AF: 0.908

Gnomad OTH AF: 0.930

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.937 AC: 142332 AN: 151858 Hom.: 66800 Cov.: 28 AF XY: 0.939 AC XY: 69678 AN XY: 74196

African (AFR) AF: 0.983 AC: 40717 AN: 41442

American (AMR) AF: 0.941 AC: 14312 AN: 15216

Ashkenazi Jewish (ASJ) AF: 0.899 AC: 3120 AN: 3472

East Asian (EAS) AF: 1.00 AC: 5165 AN: 5166

South Asian (SAS) AF: 0.921 AC: 4422 AN: 4800

European-Finnish (FIN) AF: 0.942 AC: 9899 AN: 10512

Middle Eastern (MID) AF: 0.901 AC: 265 AN: 294

European-Non Finnish (NFE) AF: 0.908 AC: 61701 AN: 67940

Other (OTH) AF: 0.928 AC: 1955 AN: 2106

Alfa AF: 0.935 Hom.: 10840

Bravo AF: 0.939

Asia WGS AF: 0.960 AC: 3339 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	0.068
DANN	Benign	0.36
PhyloP100		-3.4
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: rs2546133; hg19: chr19-6799677;