15-71215036-T-A

Position:

• chr15-71215036-T-A

Variant summary

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

The NM_024817.3(THSD4):​c.101T>A​(p.Val34Asp) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.00000354 in 1,128,972 control chromosomes in the GnomAD database, with no homozygous occurrence. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000035 (0 hom.)
• Consequence: THSD4 NM_024817.3 missense, splice_region
• Scores: Splicing: ADA: 0.2050
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.92

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 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/exons	MANE	Protein	UniProt
THSD4	NM_024817.3	c.101T>A	p.Val34Asp	missense_variant, splice_region_variant	4/18	ENST00000261862.8	NP_079093.2
THSD4	NM_001394532.1	c.101T>A	p.Val34Asp	missense_variant, splice_region_variant	4/18		NP_001381461.1
THSD4	XM_047433080.1	c.101T>A	p.Val34Asp	missense_variant, splice_region_variant	4/18		XP_047289036.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
THSD4	ENST00000261862.8	c.101T>A	p.Val34Asp	missense_variant, splice_region_variant	4/18	5	NM_024817.3	ENSP00000261862.8
THSD4	ENST00000355327.7	c.101T>A	p.Val34Asp	missense_variant, splice_region_variant	4/18	5		ENSP00000347484.3
THSD4	ENST00000620694.1	c.101T>A	p.Val34Asp	missense_variant, splice_region_variant	4/4	3		ENSP00000484438.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000354 AC: 4 AN: 1128972 Hom.: 0 Cov.: 31 AF XY: 0.00000185 AC XY: 1 AN XY: 540478

Gnomad4 AFR exome AF: 0.0000882

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: 0.00

Gnomad4 OTH exome AF: 0.0000447

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 05, 2022

The c.101T>A (p.V34D) alteration is located in exon 3 (coding exon 3) of the THSD4 gene. This alteration results from a T to A substitution at nucleotide position 101, causing the valine (V) at amino acid position 34 to be replaced by an aspartic acid (D). 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	0.48
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Uncertain	0.10
CADD	Pathogenic	26
DANN	Uncertain	0.98
DEOGEN2	Benign	0.065	T;.
Eigen	Uncertain	0.28
Eigen_PC	Uncertain	0.24
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.81	T;T
M_CAP	Uncertain	0.15	D
MetaRNN	Uncertain	0.62	D;D
MetaSVM	Benign	-0.51	T
MutationAssessor	Benign	1.1	L;.
PrimateAI	Uncertain	0.78	T
PROVEAN	Benign	-1.3	N;.
REVEL	Uncertain	0.37
Sift	Benign	0.089	T;.
Sift4G	Uncertain	0.060	T;D
Polyphen		1.0	D;.
Vest4		0.85
MutPred		0.34		Loss of catalytic residue at V34 (P = 0.0077);Loss of catalytic residue at V34 (P = 0.0077);
MVP		0.59
MPC		0.22
ClinPred		0.87	D
GERP RS		4.2
Varity_R		0.27
gMVP		0.68

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.20
dbscSNV1_RF	Benign	0.25
SpliceAI score (max)		0.020		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: chr15-71507375;