Variant 13-52377784-T-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_018676.4(THSD1):c.2186A>G(p.Tyr729Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,890 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

THSD1
NM_018676.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.222

Variant links:

Genes affected

THSD1 (HGNC:17754): (thrombospondin type 1 domain containing 1) The protein encoded by this gene contains a type 1 thrombospondin domain, which is found in a number of proteins involved in the complement pathway, as well as in extracellular matrix proteins. Alternatively spliced transcript variants encoding different isoforms have been observed for this gene. [provided by RefSeq, Jan 2009]

THSD1 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.06315988).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
THSD1	NM_018676.4 linkuse as main transcript	c.2186A>G	p.Tyr729Cys	missense_variant	5/5	ENST00000258613.5	NP_061146.1
THSD1	NM_199263.3 linkuse as main transcript	c.2027A>G	p.Tyr676Cys	missense_variant	4/4		NP_954872.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
THSD1	ENST00000258613.5 linkuse as main transcript	c.2186A>G	p.Tyr729Cys	missense_variant	5/5	1	NM_018676.4	ENSP00000258613	P1	Q9NS62-1
THSD1	ENST00000349258.8 linkuse as main transcript	c.2027A>G	p.Tyr676Cys	missense_variant	4/4	1		ENSP00000340650		Q9NS62-2
THSD1	ENST00000648254.1 linkuse as main transcript	c.2027A>G	p.Tyr676Cys	missense_variant	4/4			ENSP00000497520		Q9NS62-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461890

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727244

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

8.99e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

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

Sep 01, 2021

The c.2186A>G (p.Y729C) alteration is located in exon 5 (coding exon 4) of the THSD1 gene. This alteration results from a A to G substitution at nucleotide position 2186, causing the tyrosine (Y) at amino acid position 729 to be replaced by a cysteine (C). 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

0.077

BayesDel_addAF

Benign

-0.23

BayesDel_noAF

Benign

-0.57

CADD

Benign

9.0

DANN

Benign

0.48

DEOGEN2

Benign

0.013

.;T;.

Eigen

Benign

-0.73

Eigen_PC

Benign

-0.75

FATHMM_MKL

Benign

0.095

LIST_S2

Benign

0.73

.;T;T

M_CAP

Benign

0.024

MetaRNN

Benign

0.063

T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.85

.;L;.

MutationTaster

Benign

1.0

N;N;N

PrimateAI

Benign

0.41

PROVEAN

Uncertain

-3.0

D;N;.

REVEL

Benign

0.039

Sift

Benign

0.14

T;T;.

Sift4G

Benign

0.14

T;T;.

Polyphen

0.0070

B;B;B

Vest4

0.17

MutPred

0.17

.;Loss of phosphorylation at Y729 (P = 0.0146);.;

MVP

0.27

MPC

0.31

ClinPred

0.039

GERP RS

2.8

Varity_R

0.064

gMVP

0.14

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over