15-39588621-A-G

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2 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. 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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.387

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

Verdict is Benign. Variant got -19 ACMG points.

• PP2: Missense variant where missense usually causes diseases, THBS1
• 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	UniProt
THBS1	NM_003246.4	c.1567A>G	p.Thr523Ala	missense_variant	10/22	ENST00000260356.6
THBS1	XM_047432980.1	c.1567A>G	p.Thr523Ala	missense_variant	10/22
THBS1	XM_011521971.3	c.1472-338A>G		intron_variant

Ensembl

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

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

GnomAD3 exomes AF: 0.160 AC: 39579 AN: 248110 Hom.: 4357 AF XY: 0.158 AC XY: 21122 AN XY: 134038

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

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.: 32 AF XY: 0.214 AC XY: 15902 AN XY: 74280

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:2

Revision: criteria provided, multiple submitters, no conflicts

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 -

THBS1-related disorder Benign:1

Benign, criteria provided, single submitter

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	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
MutationTaster	Benign	1.0	P
PrimateAI	Benign	0.22	T
PROVEAN	Benign	0.29	N
REVEL	Benign	0.063
Sift	Benign	0.76	T
Sift4G	Benign	0.78	T
Polyphen		0.0	B
Vest4		0.018
MPC		0.42
ClinPred		0.0000096	T
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

Other links and lift over

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