15-39588621-A-G

Variant names:

• chr15-39588621-A-G
• rs2292305
• NM_003246.4:c.1567A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

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. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.22 (4922 hom., cov: 32)
  • Exomes 𝑓: 0.14 (17836 hom.)
• Consequence: THBS1 NM_003246.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.387
• Publications: 60 publications found

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

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

ACMG classification

Our verdict: Benign. The variant received -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 VariationId 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 rank	MANE	Protein	UniProt
THBS1	NM_003246.4	c.1567A>G	p.Thr523Ala	missense_variant	Exon 10 of 22	ENST00000260356.6	NP_003237.2
THBS1	XM_047432980.1	c.1567A>G	p.Thr523Ala	missense_variant	Exon 10 of 22		XP_047288936.1
THBS1	XM_011521971.3	c.1472-338A>G		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	c.1567A>G	p.Thr523Ala	missense_variant	Exon 10 of 22	1	NM_003246.4	ENSP00000260356.5

Frequencies

GnomAD3 genomes AF: 0.216 AC: 32869 AN: 151858 Hom.: 4913 Cov.: 32

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

GnomAD2 exomes AF: 0.160 AC: 39579 AN: 248110 AF XY: 0.158

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 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.: 32 AF XY: 0.142 AC XY: 102881 AN XY: 725278

African (AFR) AF: 0.432 AC: 14353 AN: 33240

American (AMR) AF: 0.108 AC: 4763 AN: 44228

Ashkenazi Jewish (ASJ) AF: 0.138 AC: 3585 AN: 25920

East Asian (EAS) AF: 0.349 AC: 13829 AN: 39644

South Asian (SAS) AF: 0.196 AC: 16713 AN: 85428

European-Finnish (FIN) AF: 0.103 AC: 5521 AN: 53350

Middle Eastern (MID) AF: 0.205 AC: 1166 AN: 5700

European-Non Finnish (NFE) AF: 0.122 AC: 135900 AN: 1110558

Other (OTH) AF: 0.165 AC: 9929 AN: 60248

GnomAD4 genome AF: 0.216 AC: 32901 AN: 151978 Hom.: 4922 Cov.: 32 AF XY: 0.214 AC XY: 15902 AN XY: 74280

African (AFR) AF: 0.416 AC: 17236 AN: 41386

American (AMR) AF: 0.166 AC: 2535 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.137 AC: 476 AN: 3462

East Asian (EAS) AF: 0.325 AC: 1674 AN: 5154

South Asian (SAS) AF: 0.206 AC: 990 AN: 4810

European-Finnish (FIN) AF: 0.105 AC: 1111 AN: 10600

Middle Eastern (MID) AF: 0.221 AC: 65 AN: 294

European-Non Finnish (NFE) AF: 0.121 AC: 8223 AN: 67968

Other (OTH) AF: 0.210 AC: 443 AN: 2112

Alfa AF: 0.151 Hom.: 10584

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

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: Frequency

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
AlphaMissense	Benign	0.058
BayesDel_addAF	Benign	-0.60	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	7.7
DANN	Benign	0.67
DEOGEN2	Benign	0.092	T
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.065	N
LIST_S2	Benign	0.033	T
MetaRNN	Benign	0.00024	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	-0.79	N
PhyloP100		0.39
PrimateAI	Benign	0.22	T
PROVEAN	Benign	0.29	N
REVEL	Benign	0.063
Sift	Benign	0.76	T
Sift4G	Benign	0.78	T
Vest4		0.018
ClinPred		0.0000096	T
GERP RS		-2.5
Varity_R		0.15
gMVP		0.43
Mutation Taster		=97/3	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2292305; hg19: chr15-39880822; COSMIC: COSV52950104; COSMIC: COSV52950104;