rs587777567

chr4-176711575-G-A

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_005429.5(VEGFC):c.628C>T(p.Arg210Ter) variant causes a stop gained 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 Pathogenic (★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: VEGFC NM_005429.5 stop_gained
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 5.86

Genes affected

VEGFC (HGNC:12682): (vascular endothelial growth factor C) The protein encoded by this gene is a member of the platelet-derived growth factor/vascular endothelial growth factor (PDGF/VEGF) family. The encoded protein promotes angiogenesis and endothelial cell growth, and can also affect the permeability of blood vessels. The proprotein is further cleaved into a fully processed form that can bind and activate VEGFR-2 and VEGFR-3 receptors. [provided by RefSeq, Apr 2014]

ACMG classification

Verdict is Pathogenic. Variant got 12 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 4-176711575-G-A is Pathogenic according to our data. Variant chr4-176711575-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 140737.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr4-176711575-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
VEGFC	NM_005429.5	c.628C>T	p.Arg210Ter	stop_gained	4/7	ENST00000618562.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
VEGFC	ENST00000618562.2	c.628C>T	p.Arg210Ter	stop_gained	4/7	1	NM_005429.5	P1
VEGFC	ENST00000507638.1	n.327C>T		non_coding_transcript_exon_variant	3/4	3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Lymphatic malformation 4 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jul 01, 2014

- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Sep 26, 2022

Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 30071673, 29542815, 24744435) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.63
Cadd	Pathogenic	46
Dann	Uncertain	1.0
Eigen	Pathogenic	0.98
Eigen_PC	Pathogenic	0.87
FATHMM_MKL	Uncertain	0.95	D
MutationTaster	Benign	1.0	A
Vest4		0.95
GERP RS		5.1

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

LitVar

Other links and lift over

dbSNP: rs587777567; hg19: chr4-177632729;