chr19-6772860-C-T

Variant names:

• chr19-6772860-C-T
• NM_005428.4:c.53C>T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_005428.4(VAV1):​c.53C>T​(p.Pro18Leu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. P18P) has been classified as Benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: VAV1 NM_005428.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.56

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

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.856

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VAV1	NM_005428.4	c.53C>T	p.Pro18Leu	missense_variant	Exon 1 of 27	ENST00000602142.6	NP_005419.2
VAV1	NM_001258206.2	c.53C>T	p.Pro18Leu	missense_variant	Exon 1 of 26		NP_001245135.1
VAV1	NM_001258207.2	c.53C>T	p.Pro18Leu	missense_variant	Exon 1 of 26		NP_001245136.1
VAV1	XM_005259642.2	c.53C>T	p.Pro18Leu	missense_variant	Exon 1 of 26		XP_005259699.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
VAV1	ENST00000602142.6	c.53C>T	p.Pro18Leu	missense_variant	Exon 1 of 27	1	NM_005428.4	ENSP00000472929.1
VAV1	ENST00000304076.6	c.53C>T	p.Pro18Leu	missense_variant	Exon 1 of 26	1		ENSP00000302269.2
VAV1	ENST00000596764.5	c.53C>T	p.Pro18Leu	missense_variant	Exon 1 of 26	2		ENSP00000469450.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Apr 08, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 18 of the VAV1 protein (p.Pro18Leu). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with VAV1-related conditions. An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.75
BayesDel_addAF	Uncertain	0.036	T
BayesDel_noAF	Benign	-0.19
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.90	.;D;.
Eigen	Uncertain	0.62
Eigen_PC	Uncertain	0.53
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.99	D;D;D
M_CAP	Pathogenic	0.70	D
MetaRNN	Pathogenic	0.86	D;D;D
MetaSVM	Uncertain	-0.12	T
MutationAssessor	Uncertain	2.5	.;M;M
PrimateAI	Pathogenic	0.85	D
PROVEAN	Pathogenic	-6.5	D;.;.
REVEL	Uncertain	0.42
Sift	Uncertain	0.0030	D;.;.
Sift4G	Uncertain	0.0080	D;D;D
Polyphen		1.0	.;D;.
Vest4		0.63
MutPred		0.52		Loss of catalytic residue at P18 (P = 0.0625);Loss of catalytic residue at P18 (P = 0.0625);Loss of catalytic residue at P18 (P = 0.0625);
MVP		0.49
MPC		2.0
ClinPred		0.99	D
GERP RS		4.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.81
gMVP		0.97

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr19-6772871;