15-39588617-C-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_003246.4(THBS1):c.1563C>T(p.Asn521=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0293 in 1,611,476 control chromosomes in the GnomAD database, including 790 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.022 (68 hom., cov: 32)
  • Exomes 𝑓: 0.030 (722 hom.)
• Consequence: THBS1 NM_003246.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.21

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.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.46).
• BP6: Variant 15-39588617-C-T is Benign according to our data. Variant chr15-39588617-C-T is described in ClinVar as [Benign]. Clinvar id is 403536.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=1.21 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0221 (3369/152276) while in subpopulation NFE AF= 0.0338 (2297/68002). AF 95% confidence interval is 0.0326. There are 68 homozygotes in gnomad4. There are 1531 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd at 3368 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
THBS1	NM_003246.4	c.1563C>T	p.Asn521=	synonymous_variant	10/22	ENST00000260356.6
THBS1	XM_047432980.1	c.1563C>T	p.Asn521=	synonymous_variant	10/22
THBS1	XM_011521971.3	c.1472-342C>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
THBS1	ENST00000260356.6	c.1563C>T	p.Asn521=	synonymous_variant	10/22	1	NM_003246.4	P1
THBS1-AS1	ENST00000616754.1	n.266G>A		non_coding_transcript_exon_variant	1/1
THBS1	ENST00000497720.1	n.359C>T		non_coding_transcript_exon_variant	3/3	2
FSIP1	ENST00000642527.1	c.*215-43G>A		intron_variant, NMD_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.0221 AC: 3368 AN: 152158 Hom.: 68 Cov.: 32

Gnomad AFR AF: 0.00577

Gnomad AMI AF: 0.00548

Gnomad AMR AF: 0.0308

Gnomad ASJ AF: 0.0433

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0124

Gnomad FIN AF: 0.00772

Gnomad MID AF: 0.0253

Gnomad NFE AF: 0.0338

Gnomad OTH AF: 0.0267

GnomAD3 exomes AF: 0.0238 AC: 5918 AN: 248838 Hom.: 97 AF XY: 0.0245 AC XY: 3295 AN XY: 134470

Gnomad AFR exome AF: 0.00599

Gnomad AMR exome AF: 0.0276

Gnomad ASJ exome AF: 0.0379

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0161

Gnomad FIN exome AF: 0.00858

Gnomad NFE exome AF: 0.0323

Gnomad OTH exome AF: 0.0319

GnomAD4 exome AF: 0.0301 AC: 43886 AN: 1459200 Hom.: 722 Cov.: 31 AF XY: 0.0300 AC XY: 21764 AN XY: 725820

Gnomad4 AFR exome AF: 0.00544

Gnomad4 AMR exome AF: 0.0280

Gnomad4 ASJ exome AF: 0.0365

Gnomad4 EAS exome AF: 0.0000756

Gnomad4 SAS exome AF: 0.0172

Gnomad4 FIN exome AF: 0.00978

Gnomad4 NFE exome AF: 0.0339

Gnomad4 OTH exome AF: 0.0289

GnomAD4 genome AF: 0.0221 AC: 3369 AN: 152276 Hom.: 68 Cov.: 32 AF XY: 0.0206 AC XY: 1531 AN XY: 74460

Gnomad4 AFR AF: 0.00573

Gnomad4 AMR AF: 0.0308

Gnomad4 ASJ AF: 0.0433

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.0129

Gnomad4 FIN AF: 0.00772

Gnomad4 NFE AF: 0.0338

Gnomad4 OTH AF: 0.0260

Alfa AF: 0.0276 Hom.: 31

Bravo AF: 0.0230

Asia WGS AF: 0.00549 AC: 19 AN: 3478

EpiCase AF: 0.0369

EpiControl AF: 0.0397

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: Silent, not in splice consensus -

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	-0.46
Cadd	Benign	18
Dann	Benign	0.81

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: rs41338344; hg19: chr15-39880818; COSMIC: COSV52953937; COSMIC: COSV52953937;