15-39588157-C-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_003246.4(THBS1):c.1410C>T(p.Asn470=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.147 in 1,613,928 control chromosomes in the GnomAD database, including 21,969 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.21 (4637 hom., cov: 33)
  • Exomes 𝑓: 0.14 (17332 hom.)
• Consequence: THBS1 NM_003246.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -2.07

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]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 15-39588157-C-T is Benign according to our data. Variant chr15-39588157-C-T is described in ClinVar as [Benign]. Clinvar id is 403535.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-2.07 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.396 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
THBS1	NM_003246.4	c.1410C>T	p.Asn470=	synonymous_variant	9/22	ENST00000260356.6
THBS1	XM_047432980.1	c.1410C>T	p.Asn470=	synonymous_variant	9/22
THBS1	XM_011521971.3	c.1410C>T	p.Asn470=	synonymous_variant	9/21

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
THBS1	ENST00000260356.6	c.1410C>T	p.Asn470=	synonymous_variant	9/22	1	NM_003246.4	P1
THBS1	ENST00000466755.1	n.185C>T		non_coding_transcript_exon_variant	2/2	2
THBS1	ENST00000497720.1	n.206C>T		non_coding_transcript_exon_variant	2/3	2

Frequencies

GnomAD3 genomes AF: 0.211 AC: 32111 AN: 151988 Hom.: 4634 Cov.: 33

Gnomad AFR AF: 0.401

Gnomad AMI AF: 0.162

Gnomad AMR AF: 0.164

Gnomad ASJ AF: 0.133

Gnomad EAS AF: 0.310

Gnomad SAS AF: 0.206

Gnomad FIN AF: 0.105

Gnomad MID AF: 0.222

Gnomad NFE AF: 0.121

Gnomad OTH AF: 0.209

GnomAD3 exomes AF: 0.159 AC: 39915 AN: 251390 Hom.: 4276 AF XY: 0.157 AC XY: 21381 AN XY: 135876

Gnomad AFR exome AF: 0.411

Gnomad AMR exome AF: 0.102

Gnomad ASJ exome AF: 0.135

Gnomad EAS exome AF: 0.310

Gnomad SAS exome AF: 0.198

Gnomad FIN exome AF: 0.106

Gnomad NFE exome AF: 0.117

Gnomad OTH exome AF: 0.158

GnomAD4 exome AF: 0.140 AC: 204855 AN: 1461820 Hom.: 17332 Cov.: 33 AF XY: 0.141 AC XY: 102523 AN XY: 727204

Gnomad4 AFR exome AF: 0.414

Gnomad4 AMR exome AF: 0.108

Gnomad4 ASJ exome AF: 0.134

Gnomad4 EAS exome AF: 0.330

Gnomad4 SAS exome AF: 0.196

Gnomad4 FIN exome AF: 0.104

Gnomad4 NFE exome AF: 0.122

Gnomad4 OTH exome AF: 0.163

GnomAD4 genome AF: 0.211 AC: 32134 AN: 152108 Hom.: 4637 Cov.: 33 AF XY: 0.209 AC XY: 15521 AN XY: 74352

Gnomad4 AFR AF: 0.401

Gnomad4 AMR AF: 0.164

Gnomad4 ASJ AF: 0.133

Gnomad4 EAS AF: 0.310

Gnomad4 SAS AF: 0.205

Gnomad4 FIN AF: 0.105

Gnomad4 NFE AF: 0.120

Gnomad4 OTH AF: 0.206

Alfa AF: 0.156 Hom.: 1459

Bravo AF: 0.225

Asia WGS AF: 0.264 AC: 924 AN: 3478

EpiCase AF: 0.131

EpiControl AF: 0.131

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
BayesDel_noAF	Benign	-0.80
Cadd	Benign	0.38
Dann	Benign	0.86
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs2228261; hg19: chr15-39880358; COSMIC: COSV52949871; COSMIC: COSV52949871;