15-39588617-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BS1BS2

The NM_003246.4(THBS1):c.1563C>T(p.Asn521Asn) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0293 in 1,611,476 control chromosomes in the GnomAD database, including 790 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.022 ( 68 hom., cov: 32)

Exomes 𝑓: 0.030 ( 722 hom. )

Consequence

THBS1
NM_003246.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 1.21

Publications

6 publications found

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:

THBS1-AS1 (HGNC:55224): (THBS1 antisense RNA 1)

THBS1-AS1 links:

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

FSIP1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -19 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.46).

BP6

Variant 15-39588617-C-T is Benign according to our data. Variant chr15-39588617-C-T is described in ClinVar as Benign. ClinVar VariationId is 403536.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=1.21 with no splicing effect.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0221 (3369/152276) while in subpopulation NFE AF = 0.0338 (2297/68002). AF 95% confidence interval is 0.0326. There are 68 homozygotes in GnomAd4. There are 1531 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 68 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
THBS1	NM_003246.4 link	c.1563C>T	p.Asn521Asn	synonymous_variant	Exon 10 of 22	ENST00000260356.6	NP_003237.2
THBS1	XM_047432980.1 link	c.1563C>T	p.Asn521Asn	synonymous_variant	Exon 10 of 22		XP_047288936.1
THBS1	XM_011521971.3 link	c.1472-342C>T		intron_variant	Intron 9 of 20		XP_011520273.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
THBS1	ENST00000260356.6 link	c.1563C>T	p.Asn521Asn	synonymous_variant	Exon 10 of 22	1	NM_003246.4	ENSP00000260356.5

Frequencies

GnomAD3 genomes

AF:

0.0221

AC:

3368

AN:

152158

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00577

Gnomad AMI

AF:

0.00548

Gnomad AMR

AF:

0.0308

Gnomad ASJ

AF:

0.0433

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.0124

Gnomad FIN

AF:

0.00772

Gnomad MID

AF:

0.0253

Gnomad NFE

AF:

0.0338

Gnomad OTH

AF:

0.0267

GnomAD2 exomes

AF:

0.0238

AC:

5918

AN:

248838

AF XY:

0.0245

show subpopulations

Gnomad AFR exome

AF:

0.00599

Gnomad AMR exome

AF:

0.0276

Gnomad ASJ exome

AF:

0.0379

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00858

Gnomad NFE exome

AF:

0.0323

Gnomad OTH exome

AF:

0.0319

GnomAD4 exome

AF:

0.0301

AC:

43886

AN:

1459200

Hom.:

722

Cov.:

AF XY:

0.0300

AC XY:

21764

AN XY:

725820

show subpopulations

African (AFR)

AF:

0.00544

AC:

181

AN:

33252

American (AMR)

AF:

0.0280

AC:

1239

AN:

44302

Ashkenazi Jewish (ASJ)

AF:

0.0365

AC:

947

AN:

25938

East Asian (EAS)

AF:

0.0000756

AC:

AN:

39680

South Asian (SAS)

AF:

0.0172

AC:

1471

AN:

85672

European-Finnish (FIN)

AF:

0.00978

AC:

522

AN:

53368

Middle Eastern (MID)

AF:

0.0286

AC:

164

AN:

5732

European-Non Finnish (NFE)

AF:

0.0339

AC:

37617

AN:

1110964

Other (OTH)

AF:

0.0289

AC:

1742

AN:

60292

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.493

Heterozygous variant carriers

2455

4910

7365

9820

12275

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1410

2820

4230

5640

7050

<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:

0.0221

AC:

3369

AN:

152276

Hom.:

Cov.:

AF XY:

0.0206

AC XY:

1531

AN XY:

74460

show subpopulations

African (AFR)

AF:

0.00573

AC:

238

AN:

41560

American (AMR)

AF:

0.0308

AC:

471

AN:

15308

Ashkenazi Jewish (ASJ)

AF:

0.0433

AC:

150

AN:

3466

East Asian (EAS)

AF:

0.00

AC:

AN:

5172

South Asian (SAS)

AF:

0.0129

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00772

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.0306

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0338

AC:

2297

AN:

68002

Other (OTH)

AF:

0.0260

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

170

340

509

679

849

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

114

152

190

<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:

0.0276

Hom.:

Bravo

AF:

0.0230

Asia WGS

AF:

0.00549

AC:

AN:

3478

EpiCase

AF:

0.0369

EpiControl

AF:

0.0397

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:1

Mar 28, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Silent, not in splice consensus -

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

THBS1-related disorder

Benign:1

Oct 21, 2019

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.46

CADD

Benign

(source)

DANN

Benign

0.81

PhyloP100

1.2

Mutation Taster

=100/0

polymorphism (auto)

(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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over