rs28617395

Variant names:

• chr19-6821614-C-T
• rs28617395
• NM_005428.4:c.322-8C>T

Variant summary

Our verdict is Benign. The variant received -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
• 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 -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 VariationId 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.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VAV1	NM_005428.4	MANE Select	c.322-8C>T		splice_region intron	N/A	NP_005419.2
	VAV1	NM_001258206.2		c.322-8C>T		splice_region intron	N/A	NP_001245135.1
	VAV1	NM_001258207.2		c.322-8C>T		splice_region intron	N/A	NP_001245136.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VAV1	ENST00000602142.6	TSL:1 MANE Select	c.322-8C>T		splice_region intron	N/A	ENSP00000472929.1
	VAV1	ENST00000304076.6	TSL:1	c.322-8C>T		splice_region intron	N/A	ENSP00000302269.2
	VAV1	ENST00000599806.5	TSL:1	c.157-8C>T		splice_region intron	N/A	ENSP00000472803.1

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

GnomAD2 exomes AF: 0.125 AC: 31453 AN: 251296 AF XY: 0.128

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 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

African (AFR) AF: 0.0959 AC: 3209 AN: 33478

American (AMR) AF: 0.0732 AC: 3272 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.148 AC: 3864 AN: 26130

East Asian (EAS) AF: 0.0426 AC: 1690 AN: 39700

South Asian (SAS) AF: 0.112 AC: 9618 AN: 86256

European-Finnish (FIN) AF: 0.123 AC: 6561 AN: 53418

Middle Eastern (MID) AF: 0.163 AC: 941 AN: 5764

European-Non Finnish (NFE) AF: 0.165 AC: 183418 AN: 1111850

Other (OTH) AF: 0.143 AC: 8637 AN: 60390

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

African (AFR) AF: 0.101 AC: 4193 AN: 41526

American (AMR) AF: 0.0954 AC: 1457 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.141 AC: 489 AN: 3472

East Asian (EAS) AF: 0.0441 AC: 228 AN: 5166

South Asian (SAS) AF: 0.0997 AC: 481 AN: 4826

European-Finnish (FIN) AF: 0.128 AC: 1351 AN: 10592

Middle Eastern (MID) AF: 0.168 AC: 49 AN: 292

European-Non Finnish (NFE) AF: 0.159 AC: 10799 AN: 67970

Other (OTH) AF: 0.141 AC: 298 AN: 2106

Alfa AF: 0.143 Hom.: 1429

Bravo AF: 0.127

Asia WGS AF: 0.0920 AC: 321 AN: 3478

EpiCase AF: 0.162

EpiControl AF: 0.175

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	not specified (1)
-	-	1	VAV1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	0.11
DANN	Benign	0.48
PhyloP100		-1.8
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs28617395; hg19: chr19-6821625;