19-6772995-G-A
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Variant summary
Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4BS2
The NM_005428.4(VAV1):c.188G>A(p.Arg63His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000682 in 1,613,956 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).
Frequency
Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000068 ( 0 hom. )
Consequence
VAV1
NM_005428.4 missense
NM_005428.4 missense
Scores
3
11
5
Clinical Significance
Conservation
PhyloP100: 9.33
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]
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ACMG classification
Classification made for transcript
Verdict is Likely_benign. Variant got -5 ACMG points.
BP4
Computational evidence support a benign effect (MetaRNN=0.40576655).
BS2
High AC in GnomAdExome4 at 10 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
VAV1 | NM_005428.4 | c.188G>A | p.Arg63His | missense_variant | 1/27 | ENST00000602142.6 | NP_005419.2 | |
VAV1 | NM_001258206.2 | c.188G>A | p.Arg63His | missense_variant | 1/26 | NP_001245135.1 | ||
VAV1 | NM_001258207.2 | c.188G>A | p.Arg63His | missense_variant | 1/26 | NP_001245136.1 | ||
VAV1 | XM_005259642.2 | c.188G>A | p.Arg63His | missense_variant | 1/26 | XP_005259699.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
VAV1 | ENST00000602142.6 | c.188G>A | p.Arg63His | missense_variant | 1/27 | 1 | NM_005428.4 | ENSP00000472929 | P1 | |
VAV1 | ENST00000304076.6 | c.188G>A | p.Arg63His | missense_variant | 1/26 | 1 | ENSP00000302269 | |||
VAV1 | ENST00000596764.5 | c.188G>A | p.Arg63His | missense_variant | 1/26 | 2 | ENSP00000469450 |
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152122Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.00000796 AC: 2AN: 251218Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135802
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GnomAD4 exome AF: 0.00000684 AC: 10AN: 1461834Hom.: 0 Cov.: 33 AF XY: 0.0000110 AC XY: 8AN XY: 727230
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GnomAD4 genome AF: 0.00000657 AC: 1AN: 152122Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74308
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Dec 14, 2023 | This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 63 of the VAV1 protein (p.Arg63His). This variant is present in population databases (rs771269172, gnomAD 0.006%). This variant has not been reported in the literature in individuals affected with VAV1-related conditions. ClinVar contains an entry for this variant (Variation ID: 2090973). 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:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Pathogenic
.;D;.
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Pathogenic
D;D;D
M_CAP
Uncertain
D
MetaRNN
Benign
T;T;T
MetaSVM
Benign
T
MutationAssessor
Uncertain
.;M;M
MutationTaster
Benign
D;D
PrimateAI
Uncertain
T
PROVEAN
Uncertain
D;.;.
REVEL
Uncertain
Sift
Uncertain
D;.;.
Sift4G
Uncertain
D;D;D
Polyphen
0.91
.;P;.
Vest4
MutPred
Gain of helix (P = 0.132);Gain of helix (P = 0.132);Gain of helix (P = 0.132);
MVP
MPC
2.0
ClinPred
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at