19-6772833-A-C

Variant names:

• chr19-6772833-A-C
• rs1599606651
• NM_005428.4:c.26A>C

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_005428.4(VAV1):​c.26A>C​(p.His9Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H9R) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: VAV1 NM_005428.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.497
• Publications: 0 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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.26A>C	p.His9Pro	missense	Exon 1 of 27	NP_005419.2
	VAV1	NM_001258206.2		c.26A>C	p.His9Pro	missense	Exon 1 of 26	NP_001245135.1	A0A0A0MR07
	VAV1	NM_001258207.2		c.26A>C	p.His9Pro	missense	Exon 1 of 26	NP_001245136.1	P15498-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VAV1	ENST00000602142.6	TSL:1 MANE Select	c.26A>C	p.His9Pro	missense	Exon 1 of 27	ENSP00000472929.1	P15498-1
	VAV1	ENST00000304076.6	TSL:1	c.26A>C	p.His9Pro	missense	Exon 1 of 26	ENSP00000302269.2	A0A0A0MR07
	VAV1	ENST00000962219.1		c.26A>C	p.His9Pro	missense	Exon 1 of 27	ENSP00000632278.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.68
BayesDel_addAF	Uncertain	0.013	T
BayesDel_noAF	Benign	-0.22
CADD	Benign	20
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.57	D
Eigen	Benign	-0.10
Eigen_PC	Benign	-0.043
FATHMM_MKL	Benign	0.72	D
LIST_S2	Uncertain	0.92	D
M_CAP	Uncertain	0.14	D
MetaRNN	Uncertain	0.56	D
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	0.90	L
PhyloP100		0.50
PrimateAI	Uncertain	0.56	T
PROVEAN	Benign	-1.6	N
REVEL	Uncertain	0.29
Sift	Benign	0.084	T
Sift4G	Benign	0.28	T
Polyphen		0.77	P
Vest4		0.58
MutPred		0.56		Loss of MoRF binding (P = 0.0445)
MVP		0.72
MPC		1.6
ClinPred		0.22	T
GERP RS		4.2
PromoterAI		0.077	Neutral
Varity_R		0.57
gMVP		0.96
Mutation Taster		=42/58	disease causing

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: rs1599606651; hg19: chr19-6772844;