chr15-71215248-G-GTGTC

Position:

• chr15-71215248-G-GTGTC

Variant summary

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

The NM_024817.3(THSD4):​c.314_317dup​(p.Ala107ValfsTer66) variant causes a frameshift change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 33)
• Consequence: THSD4 NM_024817.3 frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 5.09

Genes affected

THSD4 (HGNC:25835): (thrombospondin type 1 domain containing 4) Predicted to enable hydrolase activity. Predicted to be an extracellular matrix structural constituent. Predicted to act upstream of or within elastic fiber assembly. Located in collagen-containing extracellular matrix and extracellular exosome. [provided by Alliance of Genome Resources, Apr 2022]

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 15-71215248-G-GTGTC is Pathogenic according to our data. Variant chr15-71215248-G-GTGTC is described in ClinVar as [Pathogenic]. Clinvar id is 1069468.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
THSD4	NM_024817.3	c.314_317dup	p.Ala107ValfsTer66	frameshift_variant	4/18	ENST00000261862.8
THSD4	NM_001394532.1	c.314_317dup	p.Ala107ValfsTer66	frameshift_variant	4/18
THSD4	XM_047433080.1	c.314_317dup	p.Ala107ValfsTer66	frameshift_variant	4/18

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
THSD4	ENST00000261862.8	c.314_317dup	p.Ala107ValfsTer66	frameshift_variant	4/18	5	NM_024817.3	P1
THSD4	ENST00000355327.7	c.314_317dup	p.Ala107ValfsTer66	frameshift_variant	4/18	5		P1
THSD4	ENST00000620694.1			downstream_gene_variant		3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 12, 2020

For these reasons, this variant has been classified as Pathogenic. Loss-of-function variants in THSD4 are known to be pathogenic (PMID: 32855533). This variant has not been reported in the literature in individuals with THSD4-related conditions. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate insufficient coverage at this position in the ExAC database. This sequence change creates a premature translational stop signal (p.Ala107Valfs*66) in the THSD4 gene. It is expected to result in an absent or disrupted protein product. -

Computational scores

Source: dbNSFP v4.3

Splicing

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: chr15-71507587;