chr15-39588621-A-G

Position:

chr15-39588621-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_003246.4(THBS1):c.1567A>G(p.Thr523Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.148 in 1,610,294 control chromosomes in the GnomAD database, including 22,758 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

Frequency

Genomes: 𝑓 0.22 ( 4922 hom., cov: 32)

Exomes 𝑓: 0.14 ( 17836 hom. )

Consequence

THBS1
NM_003246.4 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.387

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 made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=2.3666024E-4).

BP6

Variant 15-39588621-A-G is Benign according to our data. Variant chr15-39588621-A-G is described in ClinVar as [Benign]. Clinvar id is 403537.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.411 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
THBS1	NM_003246.4 linkuse as main transcript	c.1567A>G	p.Thr523Ala	missense_variant	10/22	ENST00000260356.6
THBS1	XM_047432980.1 linkuse as main transcript	c.1567A>G	p.Thr523Ala	missense_variant	10/22
THBS1	XM_011521971.3 linkuse as main transcript	c.1472-338A>G		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
THBS1	ENST00000260356.6 linkuse as main transcript	c.1567A>G	p.Thr523Ala	missense_variant	10/22	1	NM_003246.4	P1	P07996-1
THBS1-AS1	ENST00000616754.1 linkuse as main transcript	n.262T>C		non_coding_transcript_exon_variant	1/1
THBS1	ENST00000497720.1 linkuse as main transcript	n.363A>G		non_coding_transcript_exon_variant	3/3	2
FSIP1	ENST00000642527.1 linkuse as main transcript	c.*215-47T>C		intron_variant, NMD_transcript_variant

Frequencies

GnomAD3 genomes

AF:

0.216

AC:

32869

AN:

151858

Hom.:

4913

Cov.:

show subpopulations

Gnomad AFR

AF:

0.417

Gnomad AMI

AF:

0.163

Gnomad AMR

AF:

0.166

Gnomad ASJ

AF:

0.137

Gnomad EAS

AF:

0.324

Gnomad SAS

AF:

0.206

Gnomad FIN

AF:

0.105

Gnomad MID

AF:

0.225

Gnomad NFE

AF:

0.121

Gnomad OTH

AF:

0.212

GnomAD3 exomes

AF:

0.160

AC:

39579

AN:

248110

Hom.:

4357

AF XY:

0.158

AC XY:

21122

AN XY:

134038

show subpopulations

Gnomad AFR exome

AF:

0.427

Gnomad AMR exome

AF:

0.101

Gnomad ASJ exome

AF:

0.138

Gnomad EAS exome

AF:

0.322

Gnomad SAS exome

AF:

0.195

Gnomad FIN exome

AF:

0.105

Gnomad NFE exome

AF:

0.116

Gnomad OTH exome

AF:

0.156

GnomAD4 exome

AF:

0.141

AC:

205759

AN:

1458316

Hom.:

17836

Cov.:

AF XY:

0.142

AC XY:

102881

AN XY:

725278

show subpopulations

Gnomad4 AFR exome

AF:

0.432

Gnomad4 AMR exome

AF:

0.108

Gnomad4 ASJ exome

AF:

0.138

Gnomad4 EAS exome

AF:

0.349

Gnomad4 SAS exome

AF:

0.196

Gnomad4 FIN exome

AF:

0.103

Gnomad4 NFE exome

AF:

0.122

Gnomad4 OTH exome

AF:

0.165

GnomAD4 genome

AF:

0.216

AC:

32901

AN:

151978

Hom.:

4922

Cov.:

AF XY:

0.214

AC XY:

15902

AN XY:

74280

show subpopulations

Gnomad4 AFR

AF:

0.416

Gnomad4 AMR

AF:

0.166

Gnomad4 ASJ

AF:

0.137

Gnomad4 EAS

AF:

0.325

Gnomad4 SAS

AF:

0.206

Gnomad4 FIN

AF:

0.105

Gnomad4 NFE

AF:

0.121

Gnomad4 OTH

AF:

0.210

Alfa

AF:

0.144

Hom.:

4908

Bravo

AF:

0.232

TwinsUK

AF:

0.131

AC:

486

ALSPAC

AF:

0.125

AC:

480

ESP6500AA

AF:

0.406

AC:

1785

ESP6500EA

AF:

0.132

AC:

1134

ExAC

AF:

0.166

AC:

20179

Asia WGS

AF:

0.272

AC:

950

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Mar 28, 2016

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: Frequency -

not provided

Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

- -

THBS1-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 21, 2019

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

AlphaMissense

Benign

0.058

BayesDel_addAF

Benign

-0.60

BayesDel_noAF

Benign

-0.50

CADD

Benign

7.7

DANN

Benign

0.67

DEOGEN2

Benign

0.092

Eigen

Benign

-1.5

Eigen_PC

Benign

-1.4

FATHMM_MKL

Benign

0.065

LIST_S2

Benign

0.033

MetaRNN

Benign

0.00024

MetaSVM

Benign

-0.99

MutationAssessor

Benign

-0.79

MutationTaster

Benign

1.0

PrimateAI

Benign

0.22

PROVEAN

Benign

0.29

REVEL

Benign

0.063

Sift

Benign

0.76

Sift4G

Benign

0.78

Polyphen

0.0

Vest4

0.018

MPC

0.42

ClinPred

0.0000096

GERP RS

-2.5

Varity_R

0.15

gMVP

0.43

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

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

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over