Genetic Variant THBS2:p.Ile1172Leu (chr6-169217827-T-G) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_003247.5(THBS2):c.3514A>C(p.Ile1172Leu) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000579 in 1,571,472 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. 1/1 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. I1172V) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000081 ( 0 hom., cov: 34)

Exomes 𝑓: 0.000056 ( 2 hom. )

Consequence

THBS2
NM_003247.5 missense, splice_region

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.0210

Publications

1 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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.019963145).

BS2

High AC in GnomAd4 at 9 AD gene.

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.3514A>C	p.Ile1172Leu	missense splice_region	Exon 22 of 22	NP_003238.2
THBS2	NM_001381939.1		c.3340A>C	p.Ile1114Leu	missense splice_region	Exon 21 of 21	NP_001368868.1	A0A7I2V585
THBS2	NM_001381942.1		c.3283A>C	p.Ile1095Leu	missense splice_region	Exon 22 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.3514A>C	p.Ile1172Leu	missense splice_region	Exon 22 of 22	ENSP00000482784.1	P35442
THBS2	ENST00000366787.7	TSL:1	c.3514A>C	p.Ile1172Leu	missense splice_region	Exon 23 of 23	ENSP00000355751.3	P35442
THBS2	ENST00000649844.1		c.3529A>C	p.Ile1177Leu	missense splice_region	Exon 22 of 22	ENSP00000497834.1	A0A3B3ITK0

Frequencies

GnomAD3 genomes

AF:

0.0000806

AC:

AN:

111616

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00270

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000102

AC:

AN:

225440

AF XY:

0.000138

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000184

GnomAD4 exome

AF:

0.0000562

AC:

AN:

1459780

Hom.:

Cov.:

AF XY:

0.0000785

AC XY:

AN XY:

726098

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33406

American (AMR)

AF:

0.00

AC:

AN:

44522

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26092

East Asian (EAS)

AF:

0.00

AC:

AN:

39686

South Asian (SAS)

AF:

0.000931

AC:

AN:

85894

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52740

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5678

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1111452

Other (OTH)

AF:

0.0000332

AC:

AN:

60310

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.449

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

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

AF:

0.0000806

AC:

AN:

111692

Hom.:

Cov.:

AF XY:

0.0000929

AC XY:

AN XY:

53846

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26384

American (AMR)

AF:

0.00

AC:

AN:

10178

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2796

East Asian (EAS)

AF:

0.00

AC:

AN:

4504

South Asian (SAS)

AF:

0.00271

AC:

AN:

3322

European-Finnish (FIN)

AF:

0.00

AC:

AN:

7602

Middle Eastern (MID)

AF:

0.00

AC:

AN:

200

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

54472

Other (OTH)

AF:

0.00

AC:

AN:

1512

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome 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

Alfa

AF:

0.0000494

Hom.:

Bravo

AF:

0.0000151

ExAC

AF:

0.000107

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.068

BayesDel_addAF

Benign

-0.17

BayesDel_noAF

Benign

-0.48

CADD

Benign

6.6

(source)

DANN

Benign

0.96

DEOGEN2

Uncertain

0.45

Eigen

Benign

-0.95

Eigen_PC

Benign

-0.84

FATHMM_MKL

Benign

0.38

LIST_S2

Benign

0.53

M_CAP

Benign

0.042

MetaRNN

Benign

0.020

MetaSVM

Benign

-0.99

MutationAssessor

Benign

0.34

PhyloP100

0.021

PrimateAI

Benign

0.45

PROVEAN

Benign

0.020

REVEL

Benign

0.21

Sift

Benign

0.61

Sift4G

Benign

0.13

Polyphen

0.0

Vest4

0.13

MutPred

0.42

Gain of disorder (P = 0.1361)

MVP

0.59

MPC

0.50

ClinPred

0.040

GERP RS

2.9

Varity_R

0.082

gMVP

0.21

Mutation Taster

=95/5

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

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over