15-71215264-C-T

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BS1_Supporting BS2

The NM_024817.3(THSD4):c.329C>T(p.Thr110Met) variant causes a missense change. The variant allele was found at a frequency of 0.000326 in 1,506,744 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00027 (1 hom., cov: 33)
  • Exomes 𝑓: 0.00033 (1 hom.)
• Consequence: THSD4 NM_024817.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.82

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 Benign. Variant got -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.015524834).
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00027 (41/152050) while in subpopulation AMR AF= 0.000262 (4/15260). AF 95% confidence interval is 0.000159. There are 1 homozygotes in gnomad4. There are 22 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High AC in GnomAd at 41 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
THSD4	NM_024817.3	c.329C>T	p.Thr110Met	missense_variant	4/18	ENST00000261862.8
THSD4	NM_001394532.1	c.329C>T	p.Thr110Met	missense_variant	4/18
THSD4	XM_047433080.1	c.329C>T	p.Thr110Met	missense_variant	4/18

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
THSD4	ENST00000261862.8	c.329C>T	p.Thr110Met	missense_variant	4/18	5	NM_024817.3	P1
THSD4	ENST00000355327.7	c.329C>T	p.Thr110Met	missense_variant	4/18	5		P1
THSD4	ENST00000620694.1			downstream_gene_variant		3

Frequencies

GnomAD3 genomes AF: 0.000270 AC: 41 AN: 152050 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.0208

Gnomad AMR AF: 0.000262

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: 0.000250

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000161 AC: 17 AN: 105390 Hom.: 0 AF XY: 0.000187 AC XY: 11 AN XY: 58686

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000915

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000369

Gnomad OTH exome AF: 0.000302

GnomAD4 exome AF: 0.000332 AC: 450 AN: 1354694 Hom.: 1 Cov.: 32 AF XY: 0.000331 AC XY: 221 AN XY: 667932

Gnomad4 AFR exome AF: 0.0000350

Gnomad4 AMR exome AF: 0.0000599

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: 0.000401

Gnomad4 OTH exome AF: 0.000355

GnomAD4 genome AF: 0.000270 AC: 41 AN: 152050 Hom.: 1 Cov.: 33 AF XY: 0.000296 AC XY: 22 AN XY: 74278

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.000262

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000250

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000174 Hom.: 0

Bravo AF: 0.000249

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 06, 2021

The c.329C>T (p.T110M) alteration is located in exon 3 (coding exon 3) of the THSD4 gene. This alteration results from a C to T substitution at nucleotide position 329, causing the threonine (T) at amino acid position 110 to be replaced by a methionine (M). 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	Benign	0.15
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.39
Cadd	Uncertain	24
Dann	Uncertain	0.99
DEOGEN2	Benign	0.048	T
Eigen	Benign	-0.014
Eigen_PC	Benign	-0.095
FATHMM_MKL	Benign	0.71	D
LIST_S2	Benign	0.80	T
M_CAP	Uncertain	0.26	D
MetaRNN	Benign	0.016	T
MetaSVM	Benign	-0.86	T
MutationAssessor	Benign	1.5	L
MutationTaster	Benign	1.0	N;N
PrimateAI	Pathogenic	0.93	D
PROVEAN	Benign	-0.86	N
REVEL	Benign	0.12
Sift	Benign	0.098	T
Sift4G	Benign	0.073	T
Polyphen		0.99	D
Vest4		0.30
MutPred		0.28		Loss of phosphorylation at T110 (P = 0.0546);
MVP		0.47
MPC		0.26
ClinPred		0.069	T
GERP RS		3.3
Varity_R		0.055
gMVP		0.41

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs12914419; hg19: chr15-71507603;