NM_003246.4:c.675C>T

Variant names:

• chr15-39583664-C-T
• rs112782285
• NM_003246.4:c.675C>T

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_003246.4(THBS1):​c.675C>T​(p.Asp225Asp) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0017 in 1,612,350 control chromosomes in the GnomAD database, including 48 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0093 (26 hom., cov: 32)
  • Exomes 𝑓: 0.00091 (22 hom.)
• Consequence: THBS1 NM_003246.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.0210
• Publications: 2 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 Gene-Disease associations (from GenCC):

• congenital glaucoma

  Inheritance: AD Classification: STRONG Submitted by: PanelApp Australia
• nonsyndromic genetic hearing loss

  Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.43).
• BP6: Variant 15-39583664-C-T is Benign according to our data. Variant chr15-39583664-C-T is described in ClinVar as Benign. ClinVar VariationId is 783707.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.021 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00929 (1412/152012) while in subpopulation AFR AF = 0.0324 (1343/41486). AF 95% confidence interval is 0.0309. There are 26 homozygotes in GnomAd4. There are 671 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 26 AR gene

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	THBS1	NM_003246.4	MANE Select	c.675C>T	p.Asp225Asp	synonymous	Exon 4 of 22	NP_003237.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	THBS1	ENST00000260356.6	TSL:1 MANE Select	c.675C>T	p.Asp225Asp	synonymous	Exon 4 of 22	ENSP00000260356.5	P07996-1
	THBS1	ENST00000880750.1		c.675C>T	p.Asp225Asp	synonymous	Exon 5 of 23	ENSP00000550809.1
	THBS1	ENST00000880751.1		c.675C>T	p.Asp225Asp	synonymous	Exon 5 of 23	ENSP00000550810.1

Frequencies

GnomAD3 genomes AF: 0.00916 AC: 1391 AN: 151892 Hom.: 25 Cov.: 32

Gnomad AFR AF: 0.0320

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00315

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.00575

GnomAD2 exomes AF: 0.00234 AC: 587 AN: 251370 AF XY: 0.00158

Gnomad AFR exome AF: 0.0328

Gnomad AMR exome AF: 0.00136

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000440

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.000912 AC: 1332 AN: 1460338 Hom.: 22 Cov.: 34 AF XY: 0.000771 AC XY: 560 AN XY: 726438

African (AFR) AF: 0.0330 AC: 1103 AN: 33418

American (AMR) AF: 0.00152 AC: 68 AN: 44666

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26058

East Asian (EAS) AF: 0.00 AC: 0 AN: 39622

South Asian (SAS) AF: 0.0000696 AC: 6 AN: 86236

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53250

Middle Eastern (MID) AF: 0.000521 AC: 3 AN: 5758

European-Non Finnish (NFE) AF: 0.0000108 AC: 12 AN: 1111036

Other (OTH) AF: 0.00232 AC: 140 AN: 60294

GnomAD4 genome AF: 0.00929 AC: 1412 AN: 152012 Hom.: 26 Cov.: 32 AF XY: 0.00903 AC XY: 671 AN XY: 74328

African (AFR) AF: 0.0324 AC: 1343 AN: 41486

American (AMR) AF: 0.00308 AC: 47 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5146

South Asian (SAS) AF: 0.00 AC: 0 AN: 4784

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10560

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.0000735 AC: 5 AN: 67982

Other (OTH) AF: 0.00758 AC: 16 AN: 2110

Alfa AF: 0.00439 Hom.: 12

Bravo AF: 0.0104

Asia WGS AF: 0.00693 AC: 24 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.43
CADD	Benign	13
DANN	Benign	0.83
PhyloP100		0.021
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism

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: rs112782285; hg19: chr15-39875865;