Variant 15-71215038-C-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBS1_SupportingBS2

The NM_024817.3(THSD4):c.103C>T(p.Pro35Ser) variant causes a missense change. The variant allele was found at a frequency of 0.000123 in 1,286,810 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00021 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00011 ( 1 hom. )

Consequence

THSD4
NM_024817.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.84

Variant links:

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]

THSD4 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.008051604).

BS1

Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.00021 (32/152204) while in subpopulation EAS AF= 0.00522 (27/5174). AF 95% confidence interval is 0.00368. There are 0 homozygotes in gnomad4. There are 23 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 GnomAd4 at 32 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
THSD4	NM_024817.3 linkuse as main transcript	c.103C>T	p.Pro35Ser	missense_variant	4/18	ENST00000261862.8
THSD4	NM_001394532.1 linkuse as main transcript	c.103C>T	p.Pro35Ser	missense_variant	4/18
THSD4	XM_047433080.1 linkuse as main transcript	c.103C>T	p.Pro35Ser	missense_variant	4/18

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
THSD4	ENST00000261862.8 linkuse as main transcript	c.103C>T	p.Pro35Ser	missense_variant	4/18	5	NM_024817.3	P1	Q6ZMP0-1
THSD4	ENST00000355327.7 linkuse as main transcript	c.103C>T	p.Pro35Ser	missense_variant	4/18	5		P1	Q6ZMP0-1
THSD4	ENST00000620694.1 linkuse as main transcript	c.103C>T	p.Pro35Ser	missense_variant	4/4	3

Frequencies

GnomAD3 genomes

AF:

0.000210

AC:

AN:

152094

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00520

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000240

AC:

AN:

12506

Hom.:

AF XY:

0.000165

AC XY:

AN XY:

6062

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00937

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000111

AC:

126

AN:

1134606

Hom.:

Cov.:

AF XY:

0.0000975

AC XY:

AN XY:

543646

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00427

Gnomad4 SAS exome

AF:

0.0000613

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000106

Gnomad4 OTH exome

AF:

0.000244

GnomAD4 genome

AF:

0.000210

AC:

AN:

152204

Hom.:

Cov.:

AF XY:

0.000309

AC XY:

AN XY:

74418

show subpopulations

Gnomad4 AFR

AF:

0.0000481

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00522

Gnomad4 SAS

AF:

0.000414

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000712

Hom.:

Bravo

AF:

0.000306

ExAC

AF:

0.000237

AC:

Asia WGS

AF:

0.00144

AC:

AN:

3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 03, 2023

The c.103C>T (p.P35S) 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 103, causing the proline (P) at amino acid position 35 to be replaced by a serine (S). 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

0.22

BayesDel_addAF

Benign

-0.39

BayesDel_noAF

Benign

-0.33

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.045

T;.

Eigen

Benign

0.027

Eigen_PC

Benign

0.078

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Benign

0.73

T;T

M_CAP

Benign

0.065

MetaRNN

Benign

0.0081

T;T

MetaSVM

Benign

-0.84

MutationAssessor

Benign

0.63

N;.

MutationTaster

Benign

0.74

N;N

PrimateAI

Pathogenic

0.82

PROVEAN

Benign

-1.1

N;.

REVEL

Benign

0.16

Sift

Benign

0.033

D;.

Sift4G

Benign

0.14

T;D

Polyphen

0.76

P;.

Vest4

0.38

MutPred

0.35

Gain of phosphorylation at P35 (P = 0.0341);Gain of phosphorylation at P35 (P = 0.0341);

MVP

0.57

MPC

0.16

ClinPred

0.12

GERP RS

4.4

Varity_R

0.14

gMVP

0.49

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over