chr19-6822208-T-C

Variant names:

• chr19-6822208-T-C
• rs347033
• NM_005428.4:c.450-13T>C

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.450-13T>C variant causes a 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 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -2.58
• Publications: 16 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=-0.88).
• BP6: Variant 19-6822208-T-C is Benign according to our data. Variant chr19-6822208-T-C is described in ClinVar as Benign. ClinVar VariationId 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.

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.450-13T>C		intron	N/A	NP_005419.2
	VAV1	NM_001258206.2		c.450-13T>C		intron	N/A	NP_001245135.1
	VAV1	NM_001258207.2		c.450-13T>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.450-13T>C		intron	N/A	ENSP00000472929.1
	VAV1	ENST00000304076.6	TSL:1	c.450-13T>C		intron	N/A	ENSP00000302269.2
	VAV1	ENST00000599806.5	TSL:1	c.285-13T>C		intron	N/A	ENSP00000472803.1

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

GnomAD2 exomes AF: 0.190 AC: 34138 AN: 179804 AF XY: 0.188

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 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

African (AFR) AF: 0.285 AC: 9380 AN: 32910

American (AMR) AF: 0.139 AC: 5057 AN: 36396

Ashkenazi Jewish (ASJ) AF: 0.192 AC: 4844 AN: 25238

East Asian (EAS) AF: 0.209 AC: 7960 AN: 38074

South Asian (SAS) AF: 0.161 AC: 12951 AN: 80398

European-Finnish (FIN) AF: 0.195 AC: 9795 AN: 50318

Middle Eastern (MID) AF: 0.175 AC: 791 AN: 4526

European-Non Finnish (NFE) AF: 0.201 AC: 218679 AN: 1087954

Other (OTH) AF: 0.199 AC: 11691 AN: 58728

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

African (AFR) AF: 0.280 AC: 11614 AN: 41456

American (AMR) AF: 0.162 AC: 2472 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.185 AC: 642 AN: 3472

East Asian (EAS) AF: 0.238 AC: 1220 AN: 5136

South Asian (SAS) AF: 0.156 AC: 752 AN: 4824

European-Finnish (FIN) AF: 0.202 AC: 2138 AN: 10578

Middle Eastern (MID) AF: 0.211 AC: 62 AN: 294

European-Non Finnish (NFE) AF: 0.195 AC: 13234 AN: 67938

Other (OTH) AF: 0.224 AC: 474 AN: 2112

Alfa AF: 0.198 Hom.: 12656

Bravo AF: 0.218

Asia WGS AF: 0.196 AC: 684 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	4.4
DANN	Benign	0.32
PhyloP100		-2.6
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: rs347033; hg19: chr19-6822219; COSMIC: COSV58393278; COSMIC: COSV58393278;