rs2228263

Variant names:

• chr15-39593100-T-C
• rs2228263
• NM_003246.4:c.2868T>C

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.2868T>C​(p.Asp956Asp) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.156 in 1,596,974 control chromosomes in the GnomAD database, including 20,807 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.16 (2143 hom., cov: 32)
  • Exomes 𝑓: 0.16 (18664 hom.)
• Consequence: THBS1 NM_003246.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 1.18

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]

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

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.62).
• BP6: Variant 15-39593100-T-C is Benign according to our data. Variant chr15-39593100-T-C is described in ClinVar as [Benign]. Clinvar id is 403538.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=1.18 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.199 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
THBS1	NM_003246.4	c.2868T>C	p.Asp956Asp	synonymous_variant	Exon 18 of 22	ENST00000260356.6	NP_003237.2
THBS1	XM_047432980.1	c.2868T>C	p.Asp956Asp	synonymous_variant	Exon 18 of 22		XP_047288936.1
THBS1	XM_011521971.3	c.2694T>C	p.Asp898Asp	synonymous_variant	Exon 17 of 21		XP_011520273.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
THBS1	ENST00000260356.6	c.2868T>C	p.Asp956Asp	synonymous_variant	Exon 18 of 22	1	NM_003246.4	ENSP00000260356.5
THBS1	ENST00000484734.1	n.56T>C		non_coding_transcript_exon_variant	Exon 1 of 4	5
FSIP1	ENST00000642527.1	n.*214+955A>G		intron_variant	Intron 3 of 3			ENSP00000496642.1

Frequencies

GnomAD3 genomes AF: 0.159 AC: 24128 AN: 151916 Hom.: 2136 Cov.: 32

Gnomad AFR AF: 0.203

Gnomad AMI AF: 0.110

Gnomad AMR AF: 0.117

Gnomad ASJ AF: 0.134

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.0674

Gnomad FIN AF: 0.112

Gnomad MID AF: 0.0918

Gnomad NFE AF: 0.170

Gnomad OTH AF: 0.148

GnomAD3 exomes AF: 0.127 AC: 29838 AN: 234862 Hom.: 2336 AF XY: 0.127 AC XY: 16024 AN XY: 126252

Gnomad AFR exome AF: 0.200

Gnomad AMR exome AF: 0.0842

Gnomad ASJ exome AF: 0.138

Gnomad EAS exome AF: 0.000551

Gnomad SAS exome AF: 0.0678

Gnomad FIN exome AF: 0.115

Gnomad NFE exome AF: 0.167

Gnomad OTH exome AF: 0.127

GnomAD4 exome AF: 0.155 AC: 224194 AN: 1444940 Hom.: 18664 Cov.: 33 AF XY: 0.153 AC XY: 109671 AN XY: 717568

Gnomad4 AFR exome AF: 0.202

Gnomad4 AMR exome AF: 0.0889

Gnomad4 ASJ exome AF: 0.129

Gnomad4 EAS exome AF: 0.000378

Gnomad4 SAS exome AF: 0.0721

Gnomad4 FIN exome AF: 0.118

Gnomad4 NFE exome AF: 0.171

Gnomad4 OTH exome AF: 0.146

GnomAD4 genome AF: 0.159 AC: 24165 AN: 152034 Hom.: 2143 Cov.: 32 AF XY: 0.153 AC XY: 11366 AN XY: 74340

Gnomad4 AFR AF: 0.203

Gnomad4 AMR AF: 0.117

Gnomad4 ASJ AF: 0.134

Gnomad4 EAS AF: 0.000386

Gnomad4 SAS AF: 0.0673

Gnomad4 FIN AF: 0.112

Gnomad4 NFE AF: 0.170

Gnomad4 OTH AF: 0.148

Alfa AF: 0.164 Hom.: 2504

Bravo AF: 0.159

Asia WGS AF: 0.0500 AC: 174 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 22, 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
BayesDel_noAF	Benign	-0.62
CADD	Benign	8.8
DANN	Benign	0.77
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: rs2228263; hg19: chr15-39885301; COSMIC: COSV52951928; COSMIC: COSV52951928;