dbSNP rs1235555031: THBS3:p.Val892Leu (chr1-155196125-C-A) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_007112.5(THBS3):c.2674G>T(p.Val892Leu) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,694 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V892M) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

THBS3
NM_007112.5 missense, splice_region

Scores

Splicing: ADA: 0.2630

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 7.62

Variant links:

Genes affected

THBS3 (HGNC:11787): (thrombospondin 3) The protein encoded by this gene belongs to the thrombospondin family. Thrombospondin family members are adhesive glycoproteins that mediate cell-to-cell and cell-to-matrix interactions. This protein forms a pentameric molecule linked by a single disulfide bond. This gene shares a common promoter with metaxin 1. Alternate splicing results in coding and non-coding transcript variants. [provided by RefSeq, Nov 2011]

THBS3 links:

THBS3-AS1 (HGNC:40582): (THBS3 antisense RNA 1)

THBS3-AS1 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.42281532).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
THBS3	NM_007112.5 link	c.2674G>T	p.Val892Leu	missense_variant, splice_region_variant	Exon 22 of 23	ENST00000368378.7	NP_009043.1	P49746-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
THBS3	ENST00000368378.7 link	c.2674G>T	p.Val892Leu	missense_variant, splice_region_variant	Exon 22 of 23	1	NM_007112.5	ENSP00000357362.3		P49746-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

251366

Hom.:

AF XY:

0.00000736

AC XY:

AN XY:

135844

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000544

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:

6.84e-7

AC:

AN:

1461694

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727146

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:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.29

BayesDel_addAF

Benign

-0.049

BayesDel_noAF

Benign

-0.14

CADD

Uncertain

DANN

Uncertain

0.97

DEOGEN2

Uncertain

0.51

D;.;.;.

Eigen

Benign

-0.20

Eigen_PC

Benign

-0.033

FATHMM_MKL

Uncertain

0.87

LIST_S2

Uncertain

0.95

D;D;D;D

M_CAP

Uncertain

0.13

MetaRNN

Benign

0.42

T;T;T;T

MetaSVM

Uncertain

-0.19

MutationAssessor

Benign

0.74

N;.;.;.

PrimateAI

Uncertain

0.65

PROVEAN

Benign

-1.1

N;.;N;N

REVEL

Uncertain

0.32

Sift

Benign

0.26

T;.;T;T

Sift4G

Benign

0.34

T;T;T;T

Polyphen

0.010

B;.;.;.

Vest4

0.53

MutPred

0.78

Loss of MoRF binding (P = 0.1023);.;.;.;

MVP

0.60

MPC

0.36

ClinPred

0.56

GERP RS

3.5

Varity_R

0.16

gMVP

0.54

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.26

dbscSNV1_RF

Benign

0.51

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

Computational scores

Splicing

Publications

LitVar

Other links and lift over