15-71215293-G-T

Position:

• chr15-71215293-G-T

Variant summary

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

The NM_024817.3(THSD4):​c.358G>T​(p.Glu120Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000073 in 1,370,416 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.3e-7 (0 hom.)
• Consequence: THSD4 NM_024817.3 stop_gained
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 0.587

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 15-71215293-G-T is Pathogenic according to our data. Variant chr15-71215293-G-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 3236718.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
THSD4	NM_024817.3	c.358G>T	p.Glu120Ter	stop_gained	4/18	ENST00000261862.8	NP_079093.2
THSD4	NM_001394532.1	c.358G>T	p.Glu120Ter	stop_gained	4/18		NP_001381461.1
THSD4	XM_047433080.1	c.358G>T	p.Glu120Ter	stop_gained	4/18		XP_047289036.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
THSD4	ENST00000261862.8	c.358G>T	p.Glu120Ter	stop_gained	4/18	5	NM_024817.3	ENSP00000261862	P1
THSD4	ENST00000355327.7	c.358G>T	p.Glu120Ter	stop_gained	4/18	5		ENSP00000347484	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 7.30e-7 AC: 1 AN: 1370416 Hom.: 0 Cov.: 32 AF XY: 0.00000148 AC XY: 1 AN XY: 675864

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.32e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Aortic aneurysm, familial thoracic 12 Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Centre of Medical Genetics, University of Antwerp

May 21, 2024

PVS1, PM2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Uncertain	0.050
CADD	Pathogenic	33
DANN	Uncertain	0.98
Eigen	Benign	-0.28
Eigen_PC	Benign	-0.61
FATHMM_MKL	Benign	0.33	N
MutationTaster	Benign	1.0	A;A
Vest4		0.14
GERP RS		0.34

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: chr15-71507632;