rs2229364

Variant names:

• chr15-39587516-G-A
• rs2229364
• NM_003246.4:c.1290G>A

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_003246.4(THBS1):​c.1290G>A​(p.Lys430Lys) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.13 in 1,610,996 control chromosomes in the GnomAD database, including 15,362 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.12 (1280 hom., cov: 33)
  • Exomes 𝑓: 0.13 (14082 hom.)
• Consequence: THBS1 NM_003246.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 2.47
• Publications: 19 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]

THBS1-IT1 (HGNC:55225): (THBS1 intronic transcript 1)

ACMG classification

Our verdict: Benign. The variant received -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.43).
• BP6: Variant 15-39587516-G-A is Benign according to our data. Variant chr15-39587516-G-A is described in ClinVar as Benign. ClinVar VariationId is 403534.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=2.47 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.298 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.1290G>A	p.Lys430Lys	synonymous	Exon 8 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.1290G>A	p.Lys430Lys	synonymous	Exon 8 of 22	ENSP00000260356.5
	THBS1	ENST00000466755.1	TSL:2	n.65G>A		non_coding_transcript_exon	Exon 1 of 2
	THBS1	ENST00000497720.1	TSL:2	n.86G>A		non_coding_transcript_exon	Exon 1 of 3

Frequencies

GnomAD3 genomes AF: 0.120 AC: 18276 AN: 152168 Hom.: 1284 Cov.: 33

Gnomad AFR AF: 0.0820

Gnomad AMI AF: 0.159

Gnomad AMR AF: 0.134

Gnomad ASJ AF: 0.133

Gnomad EAS AF: 0.311

Gnomad SAS AF: 0.205

Gnomad FIN AF: 0.105

Gnomad MID AF: 0.206

Gnomad NFE AF: 0.120

Gnomad OTH AF: 0.138

GnomAD2 exomes AF: 0.134 AC: 33218 AN: 247448 AF XY: 0.139

Gnomad AFR exome AF: 0.0787

Gnomad AMR exome AF: 0.0898

Gnomad ASJ exome AF: 0.135

Gnomad EAS exome AF: 0.307

Gnomad FIN exome AF: 0.105

Gnomad NFE exome AF: 0.116

Gnomad OTH exome AF: 0.146

GnomAD4 exome AF: 0.131 AC: 190797 AN: 1458710 Hom.: 14082 Cov.: 32 AF XY: 0.133 AC XY: 96335 AN XY: 725150

African (AFR) AF: 0.0880 AC: 2942 AN: 33434

American (AMR) AF: 0.0929 AC: 4132 AN: 44500

Ashkenazi Jewish (ASJ) AF: 0.134 AC: 3506 AN: 26068

East Asian (EAS) AF: 0.330 AC: 13039 AN: 39560

South Asian (SAS) AF: 0.195 AC: 16704 AN: 85838

European-Finnish (FIN) AF: 0.104 AC: 5506 AN: 53190

Middle Eastern (MID) AF: 0.190 AC: 1092 AN: 5756

European-Non Finnish (NFE) AF: 0.122 AC: 135253 AN: 1110082

Other (OTH) AF: 0.143 AC: 8623 AN: 60282

GnomAD4 genome AF: 0.120 AC: 18266 AN: 152286 Hom.: 1280 Cov.: 33 AF XY: 0.122 AC XY: 9120 AN XY: 74466

African (AFR) AF: 0.0819 AC: 3405 AN: 41564

American (AMR) AF: 0.134 AC: 2055 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.133 AC: 463 AN: 3472

East Asian (EAS) AF: 0.311 AC: 1609 AN: 5176

South Asian (SAS) AF: 0.204 AC: 985 AN: 4828

European-Finnish (FIN) AF: 0.105 AC: 1116 AN: 10606

Middle Eastern (MID) AF: 0.201 AC: 59 AN: 294

European-Non Finnish (NFE) AF: 0.120 AC: 8142 AN: 68016

Other (OTH) AF: 0.136 AC: 287 AN: 2114

Alfa AF: 0.116 Hom.: 832

Bravo AF: 0.122

Asia WGS AF: 0.247 AC: 863 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	-0.43
CADD	Benign	13
DANN	Benign	0.92
PhyloP100		2.5
Mutation Taster		=100/0	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: rs2229364; hg19: chr15-39879717; COSMIC: COSV52950132; COSMIC: COSV52950132;