chr15-39593100-T-C

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 18 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]

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

ACMG classification

Our verdict: Benign. The variant received -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 VariationId 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003246.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	THBS1	NM_003246.4	MANE Select	c.2868T>C	p.Asp956Asp	synonymous	Exon 18 of 22	NP_003237.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	THBS1	ENST00000260356.6	TSL:1 MANE Select	c.2868T>C	p.Asp956Asp	synonymous	Exon 18 of 22	ENSP00000260356.5
	THBS1	ENST00000880750.1		c.2868T>C	p.Asp956Asp	synonymous	Exon 19 of 23	ENSP00000550809.1
	THBS1	ENST00000880751.1		c.2868T>C	p.Asp956Asp	synonymous	Exon 19 of 23	ENSP00000550810.1

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

GnomAD2 exomes AF: 0.127 AC: 29838 AN: 234862 AF XY: 0.127

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 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

African (AFR) AF: 0.202 AC: 6667 AN: 32942

American (AMR) AF: 0.0889 AC: 3795 AN: 42698

Ashkenazi Jewish (ASJ) AF: 0.129 AC: 3186 AN: 24640

East Asian (EAS) AF: 0.000378 AC: 15 AN: 39638

South Asian (SAS) AF: 0.0721 AC: 5964 AN: 82698

European-Finnish (FIN) AF: 0.118 AC: 6206 AN: 52630

Middle Eastern (MID) AF: 0.110 AC: 620 AN: 5660

European-Non Finnish (NFE) AF: 0.171 AC: 189006 AN: 1104396

Other (OTH) AF: 0.146 AC: 8735 AN: 59638

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

African (AFR) AF: 0.203 AC: 8410 AN: 41414

American (AMR) AF: 0.117 AC: 1789 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.134 AC: 465 AN: 3466

East Asian (EAS) AF: 0.000386 AC: 2 AN: 5186

South Asian (SAS) AF: 0.0673 AC: 324 AN: 4816

European-Finnish (FIN) AF: 0.112 AC: 1188 AN: 10590

Middle Eastern (MID) AF: 0.0952 AC: 28 AN: 294

European-Non Finnish (NFE) AF: 0.170 AC: 11547 AN: 67970

Other (OTH) AF: 0.148 AC: 312 AN: 2110

Alfa AF: 0.164 Hom.: 3140

Bravo AF: 0.159

Asia WGS AF: 0.0500 AC: 174 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)
-	-	1	not specified (1)
-	-	1	THBS1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.62
CADD	Benign	8.8
DANN	Benign	0.77
PhyloP100		1.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=99/1	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: rs2228263; hg19: chr15-39885301; COSMIC: COSV52951928; COSMIC: COSV52951928;