Genetic Variant NM_003247.5:c.3187G>C (chr6-169222283-C-G) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

The NM_003247.5(THBS2):c.3187G>C(p.Val1063Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,460,984 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 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. V1063M) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

THBS2
NM_003247.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 4.49

Publications

0 publications found

Variant links:

Genes affected

THBS2 (HGNC:11786): (thrombospondin 2) The protein encoded by this gene belongs to the thrombospondin family. It is a disulfide-linked homotrimeric glycoprotein that mediates cell-to-cell and cell-to-matrix interactions. This protein has been shown to function as a potent inhibitor of tumor growth and angiogenesis. Studies of the mouse counterpart suggest that this protein may modulate the cell surface properties of mesenchymal cells and be involved in cell adhesion and migration. [provided by RefSeq, Jul 2008]

THBS2 links:

THBS2-AS1 (HGNC:56059): (THBS2 antisense RNA 1)

THBS2-AS1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.3973037).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003247.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
THBS2	NM_003247.5	MANE Select	c.3187G>C	p.Val1063Leu	missense	Exon 19 of 22	NP_003238.2
THBS2	NM_001381939.1		c.3013G>C	p.Val1005Leu	missense	Exon 18 of 21	NP_001368868.1	A0A7I2V585
THBS2	NM_001381942.1		c.2956G>C	p.Val986Leu	missense	Exon 19 of 22	NP_001368871.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
THBS2	ENST00000617924.6	TSL:1 MANE Select	c.3187G>C	p.Val1063Leu	missense	Exon 19 of 22	ENSP00000482784.1	P35442
THBS2	ENST00000366787.7	TSL:1	c.3187G>C	p.Val1063Leu	missense	Exon 20 of 23	ENSP00000355751.3	P35442
THBS2	ENST00000649844.1		c.3202G>C	p.Val1068Leu	missense	Exon 19 of 22	ENSP00000497834.1	A0A3B3ITK0

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1460984

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

726794

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52536

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

8.99e-7

AC:

AN:

1112006

Other (OTH)

AF:

0.00

AC:

AN:

60380

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.32

BayesDel_addAF

Uncertain

0.077

BayesDel_noAF

Benign

-0.13

CADD

Benign

(source)

DANN

Benign

0.94

DEOGEN2

Uncertain

0.46

Eigen

Benign

0.018

Eigen_PC

Benign

0.068

FATHMM_MKL

Uncertain

0.93

LIST_S2

Benign

0.71

M_CAP

Benign

0.083

MetaRNN

Benign

0.40

MetaSVM

Uncertain

0.23

MutationAssessor

Benign

-0.28

PhyloP100

4.5

PrimateAI

Uncertain

0.75

PROVEAN

Benign

-0.050

REVEL

Uncertain

0.39

Sift

Benign

1.0

Sift4G

Benign

1.0

Polyphen

0.99

Vest4

0.33

MutPred

0.68

Loss of sheet (P = 0.0817)

MVP

0.92

MPC

0.84

ClinPred

0.75

GERP RS

4.3

Varity_R

0.16

gMVP

0.57

Mutation Taster

=72/28

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over