Genetic Variant NM_003246.4:c.2099A>G (chr15-39589977-A-G) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_003246.4(THBS1):c.2099A>G(p.Asn700Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.104 in 1,613,160 control chromosomes in the GnomAD database, including 9,683 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.079 ( 651 hom., cov: 32)

Exomes 𝑓: 0.11 ( 9032 hom. )

Consequence

THBS1
NM_003246.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 9.32

Publications

85 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:

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 -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0038629174).

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.117 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
THBS1	NM_003246.4 link	c.2099A>G	p.Asn700Ser	missense_variant	Exon 13 of 22	ENST00000260356.6	NP_003237.2
THBS1	XM_047432980.1 link	c.2099A>G	p.Asn700Ser	missense_variant	Exon 13 of 22		XP_047288936.1
THBS1	XM_011521971.3 link	c.1925A>G	p.Asn642Ser	missense_variant	Exon 12 of 21		XP_011520273.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
THBS1	ENST00000260356.6 link	c.2099A>G	p.Asn700Ser	missense_variant	Exon 13 of 22	1	NM_003246.4	ENSP00000260356.5
FSIP1	ENST00000642527.1 link	n.*215-1403T>C		intron_variant	Intron 3 of 3			ENSP00000496642.1
THBS1	ENST00000490247.1 link	n.*134A>G		downstream_gene_variant		2

Frequencies

GnomAD3 genomes

AF:

0.0795

AC:

12093

AN:

152198

Hom.:

652

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0301

Gnomad AMI

AF:

0.0888

Gnomad AMR

AF:

0.0627

Gnomad ASJ

AF:

0.0582

Gnomad EAS

AF:

0.000385

Gnomad SAS

AF:

0.0520

Gnomad FIN

AF:

0.0974

Gnomad MID

AF:

0.0443

Gnomad NFE

AF:

0.120

Gnomad OTH

AF:

0.0780

GnomAD2 exomes

AF:

0.0793

AC:

19725

AN:

248600

AF XY:

0.0814

show subpopulations

Gnomad AFR exome

AF:

0.0301

Gnomad AMR exome

AF:

0.0417

Gnomad ASJ exome

AF:

0.0592

Gnomad EAS exome

AF:

0.000491

Gnomad FIN exome

AF:

0.0982

Gnomad NFE exome

AF:

0.117

Gnomad OTH exome

AF:

0.0806

GnomAD4 exome

AF:

0.106

AC:

155200

AN:

1460844

Hom.:

9032

Cov.:

AF XY:

0.105

AC XY:

76082

AN XY:

726602

show subpopulations

African (AFR)

AF:

0.0253

AC:

845

AN:

33450

American (AMR)

AF:

0.0446

AC:

1989

AN:

44626

Ashkenazi Jewish (ASJ)

AF:

0.0572

AC:

1494

AN:

26108

East Asian (EAS)

AF:

0.000277

AC:

AN:

39676

South Asian (SAS)

AF:

0.0523

AC:

4499

AN:

86076

European-Finnish (FIN)

AF:

0.101

AC:

5376

AN:

53360

Middle Eastern (MID)

AF:

0.0537

AC:

308

AN:

5738

European-Non Finnish (NFE)

AF:

0.122

AC:

135159

AN:

1111452

Other (OTH)

AF:

0.0914

AC:

5519

AN:

60358

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.484

Heterozygous variant carriers

7752

15504

23257

31009

38761

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

4734

9468

14202

18936

23670

<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:

0.0794

AC:

12088

AN:

152316

Hom.:

651

Cov.:

AF XY:

0.0772

AC XY:

5748

AN XY:

74474

show subpopulations

African (AFR)

AF:

0.0300

AC:

1249

AN:

41576

American (AMR)

AF:

0.0626

AC:

957

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.0582

AC:

202

AN:

3470

East Asian (EAS)

AF:

0.000386

AC:

AN:

5186

South Asian (SAS)

AF:

0.0516

AC:

249

AN:

4826

European-Finnish (FIN)

AF:

0.0974

AC:

1035

AN:

10624

Middle Eastern (MID)

AF:

0.0442

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.120

AC:

8138

AN:

68022

Other (OTH)

AF:

0.0767

AC:

162

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

572

1144

1715

2287

2859

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

144

288

432

576

720

<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:

0.102

Hom.:

4147

Bravo

AF:

0.0734

TwinsUK

AF:

0.129

AC:

480

ESP6500AA

AF:

0.0361

AC:

159

ESP6500EA

AF:

0.114

AC:

982

ExAC

AF:

0.0808

AC:

9807

Asia WGS

AF:

0.0220

AC:

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.17

BayesDel_addAF

Benign

-0.35

BayesDel_noAF

Benign

-0.17

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.67

Eigen

Pathogenic

0.85

Eigen_PC

Pathogenic

0.85

LIST_S2

Uncertain

0.95

MetaRNN

Benign

0.0039

MetaSVM

Benign

-0.57

MutationAssessor

Benign

1.5

PhyloP100

9.3

PrimateAI

Uncertain

0.53

PROVEAN

Uncertain

-2.6

Sift

Uncertain

0.027

Sift4G

Uncertain

0.0060

Vest4

0.29

ClinPred

0.027

GERP RS

6.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.16

gMVP

0.81

Mutation Taster

=70/30

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.050

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

Computational scores

Splicing

Publications

Other links and lift over