chr19-6772975-C-A

Variant names:

• chr19-6772975-C-A
• NM_005428.4:c.168C>A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_005428.4(VAV1):​c.168C>A​(p.Asn56Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,844 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. N56N) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: VAV1 NM_005428.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.99

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 2 ACMG points.

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VAV1	NM_005428.4	c.168C>A	p.Asn56Lys	missense_variant	Exon 1 of 27	ENST00000602142.6	NP_005419.2
VAV1	NM_001258206.2	c.168C>A	p.Asn56Lys	missense_variant	Exon 1 of 26		NP_001245135.1
VAV1	NM_001258207.2	c.168C>A	p.Asn56Lys	missense_variant	Exon 1 of 26		NP_001245136.1
VAV1	XM_005259642.2	c.168C>A	p.Asn56Lys	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.168C>A	p.Asn56Lys	missense_variant	Exon 1 of 27	1	NM_005428.4	ENSP00000472929.1
VAV1	ENST00000304076.6	c.168C>A	p.Asn56Lys	missense_variant	Exon 1 of 26	1		ENSP00000302269.2
VAV1	ENST00000596764.5	c.168C>A	p.Asn56Lys	missense_variant	Exon 1 of 26	2		ENSP00000469450.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461844 Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1 AN XY: 727238

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.77
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.42
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.76	.;D;.
Eigen	Uncertain	0.23
Eigen_PC	Benign	0.17
FATHMM_MKL	Benign	0.71	D
LIST_S2	Uncertain	0.95	D;D;D
M_CAP	Uncertain	0.28	D
MetaRNN	Uncertain	0.51	D;D;D
MetaSVM	Benign	-0.67	T
MutationAssessor	Benign	0.67	.;N;N
PrimateAI	Uncertain	0.76	T
PROVEAN	Uncertain	-2.9	D;.;.
REVEL	Benign	0.29
Sift	Uncertain	0.014	D;.;.
Sift4G	Uncertain	0.023	D;D;D
Polyphen		0.88	.;P;.
Vest4		0.44
MutPred		0.64		Gain of ubiquitination at N56 (P = 0.03);Gain of ubiquitination at N56 (P = 0.03);Gain of ubiquitination at N56 (P = 0.03);
MVP		0.57
MPC		2.1
ClinPred		0.99	D
GERP RS		1.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.47
gMVP		0.81

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: chr19-6772986;