15-39593094-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2PP2BP4

The NM_003246.4(THBS1):c.2862G>C(p.Glu954Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000138 in 1,446,882 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: not found (cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

THBS1
NM_003246.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.697

Variant links:

Genes affected

THBS1 (HGNC:11785): (thrombospondin 1) The protein encoded by this gene is a subunit of a disulfide-linked homotrimeric protein. This protein is an adhesive glycoprotein that mediates cell-to-cell and cell-to-matrix interactions. This protein can bind to fibrinogen, fibronectin, laminin, type V collagen and integrins alpha-V/beta-1. This protein has been shown to play roles in platelet aggregation, angiogenesis, and tumorigenesis. [provided by RefSeq, Jul 2008]

THBS1 links:

FSIP1 (HGNC:21674): (fibrous sheath interacting protein 1)

FSIP1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP2

Missense variant where missense usually causes diseases, THBS1

BP4

Computational evidence support a benign effect (MetaRNN=0.32053852).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
THBS1	NM_003246.4 linkuse as main transcript	c.2862G>C	p.Glu954Asp	missense_variant	18/22	ENST00000260356.6
THBS1	XM_047432980.1 linkuse as main transcript	c.2862G>C	p.Glu954Asp	missense_variant	18/22
THBS1	XM_011521971.3 linkuse as main transcript	c.2688G>C	p.Glu896Asp	missense_variant	17/21

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
THBS1	ENST00000260356.6 linkuse as main transcript	c.2862G>C	p.Glu954Asp	missense_variant	18/22	1	NM_003246.4	P1	P07996-1
THBS1	ENST00000484734.1 linkuse as main transcript	n.50G>C		non_coding_transcript_exon_variant	1/4	5
FSIP1	ENST00000642527.1 linkuse as main transcript	c.*214+961C>G		intron_variant, NMD_transcript_variant

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000127

AC:

AN:

235706

Hom.:

AF XY:

0.0000158

AC XY:

AN XY:

126742

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000550

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000186

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000138

AC:

AN:

1446882

Hom.:

Cov.:

AF XY:

0.00000139

AC XY:

AN XY:

718740

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

9.05e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000480

Hom.:

Bravo

AF:

0.00000378

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 06, 2022

The c.2862G>C (p.E954D) alteration is located in exon 18 (coding exon 17) of the THBS1 gene. This alteration results from a G to C substitution at nucleotide position 2862, causing the glutamic acid (E) at amino acid position 954 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

Benign

0.24

BayesDel_addAF

Benign

-0.061

BayesDel_noAF

Benign

-0.15

Cadd

Benign

Dann

Uncertain

0.99

DEOGEN2

Benign

0.31

Eigen

Benign

-0.15

Eigen_PC

Benign

-0.036

FATHMM_MKL

Benign

0.64

LIST_S2

Uncertain

0.96

M_CAP

Benign

0.017

MetaRNN

Benign

0.32

MetaSVM

Benign

-0.57

MutationAssessor

Uncertain

2.1

MutationTaster

Benign

0.78

PrimateAI

Pathogenic

0.81

PROVEAN

Benign

-1.5

REVEL

Uncertain

0.37

Sift

Benign

0.31

Sift4G

Benign

0.41

Polyphen

0.24

Vest4

0.61

MutPred

0.20

Gain of sheet (P = 0.1208);

MVP

0.83

MPC

0.70

ClinPred

0.20

GERP RS

3.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.31

gMVP

0.63

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.060

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