14-76776052-C-T

Variant names:

• chr14-76776052-C-T
• rs1254632652
• NM_014909.5:c.691C>T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_014909.5(VASH1):​c.691C>T​(p.Pro231Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00000657 in 152,262 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: 33)
• Consequence: VASH1 NM_014909.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.89

Genes affected

VASH1 (HGNC:19964): (vasohibin 1) Enables actin binding activity and metallocarboxypeptidase activity. Involved in negative regulation of angiogenesis; negative regulation of blood vessel endothelial cell migration; and proteolysis. Acts upstream of or within several processes, including negative regulation of endothelial cell migration; negative regulation of endothelial cell proliferation; and negative regulation of lymphangiogenesis. Located in apical part of cell; endoplasmic reticulum; and extracellular space. Implicated in liver cirrhosis and portal hypertension. Biomarker of liver cirrhosis. [provided by Alliance of Genome Resources, Apr 2022]

ENSG00000259081 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.2961693).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VASH1	NM_014909.5	c.691C>T	p.Pro231Ser	missense_variant	Exon 5 of 7	ENST00000167106.9	NP_055724.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
VASH1	ENST00000167106.9	c.691C>T	p.Pro231Ser	missense_variant	Exon 5 of 7	1	NM_014909.5	ENSP00000167106.4
VASH1	ENST00000556038.5	n.464C>T		non_coding_transcript_exon_variant	Exon 4 of 5	5
ENSG00000259081	ENST00000556368.1	n.120-1139G>A		intron_variant	Intron 1 of 1	2

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152262 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 32

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152262 Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1 AN XY: 74382

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Nov 13, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.691C>T (p.P231S) alteration is located in exon 5 (coding exon 5) of the VASH1 gene. This alteration results from a C to T substitution at nucleotide position 691, causing the proline (P) at amino acid position 231 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.56
BayesDel_addAF	Benign	-0.016	T
BayesDel_noAF	Benign	-0.26
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.18	T
Eigen	Benign	0.13
Eigen_PC	Uncertain	0.29
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Uncertain	0.89	D
M_CAP	Benign	0.0047	T
MetaRNN	Benign	0.30	T
MetaSVM	Benign	-0.74	T
MutationAssessor	Benign	0.69	N
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	0.56	N
REVEL	Benign	0.29
Sift	Benign	0.032	D
Sift4G	Benign	0.28	T
Polyphen		0.19	B
Vest4		0.58
MutPred		0.26		Loss of catalytic residue at P230 (P = 0.016);
MVP		0.068
MPC		0.80
ClinPred		0.60	D
GERP RS		5.2
Varity_R		0.28
gMVP		0.66

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1254632652; hg19: chr14-77242395;