NM_003246.4:c.903+24C>T

Variant names:

• chr15-39584211-C-T
• rs7170682
• NM_003246.4:c.903+24C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_003246.4(THBS1):​c.903+24C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.153 in 1,613,628 control chromosomes in the GnomAD database, including 25,753 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.24 (6466 hom., cov: 33)
  • Exomes 𝑓: 0.14 (19287 hom.)
• Consequence: THBS1 NM_003246.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.14
• Publications: 8 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):

• nonsyndromic genetic hearing loss

  Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.76).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.49 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
THBS1	NM_003246.4	c.903+24C>T		intron_variant	Intron 5 of 21	ENST00000260356.6	NP_003237.2
THBS1	XM_047432980.1	c.903+24C>T		intron_variant	Intron 5 of 21		XP_047288936.1
THBS1	XM_011521971.3	c.903+24C>T		intron_variant	Intron 5 of 20		XP_011520273.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
THBS1	ENST00000260356.6	c.903+24C>T		intron_variant	Intron 5 of 21	1	NM_003246.4	ENSP00000260356.5

Frequencies

GnomAD3 genomes AF: 0.239 AC: 36349 AN: 152068 Hom.: 6455 Cov.: 33

Gnomad AFR AF: 0.496

Gnomad AMI AF: 0.162

Gnomad AMR AF: 0.173

Gnomad ASJ AF: 0.136

Gnomad EAS AF: 0.325

Gnomad SAS AF: 0.207

Gnomad FIN AF: 0.105

Gnomad MID AF: 0.218

Gnomad NFE AF: 0.121

Gnomad OTH AF: 0.228

GnomAD2 exomes AF: 0.167 AC: 41828 AN: 250886 AF XY: 0.163

Gnomad AFR exome AF: 0.500

Gnomad AMR exome AF: 0.106

Gnomad ASJ exome AF: 0.140

Gnomad EAS exome AF: 0.324

Gnomad FIN exome AF: 0.106

Gnomad NFE exome AF: 0.118

Gnomad OTH exome AF: 0.160

GnomAD4 exome AF: 0.144 AC: 209804 AN: 1461442 Hom.: 19287 Cov.: 33 AF XY: 0.144 AC XY: 104667 AN XY: 726950

African (AFR) AF: 0.516 AC: 17291 AN: 33478

American (AMR) AF: 0.113 AC: 5051 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.138 AC: 3599 AN: 26128

East Asian (EAS) AF: 0.344 AC: 13660 AN: 39684

South Asian (SAS) AF: 0.196 AC: 16880 AN: 86244

European-Finnish (FIN) AF: 0.104 AC: 5543 AN: 53348

Middle Eastern (MID) AF: 0.210 AC: 1214 AN: 5768

European-Non Finnish (NFE) AF: 0.123 AC: 136257 AN: 1111692

Other (OTH) AF: 0.171 AC: 10309 AN: 60384

GnomAD4 genome AF: 0.239 AC: 36393 AN: 152186 Hom.: 6466 Cov.: 33 AF XY: 0.237 AC XY: 17614 AN XY: 74412

African (AFR) AF: 0.496 AC: 20556 AN: 41474

American (AMR) AF: 0.173 AC: 2638 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.136 AC: 473 AN: 3472

East Asian (EAS) AF: 0.325 AC: 1688 AN: 5186

South Asian (SAS) AF: 0.206 AC: 994 AN: 4826

European-Finnish (FIN) AF: 0.105 AC: 1118 AN: 10604

Middle Eastern (MID) AF: 0.214 AC: 63 AN: 294

European-Non Finnish (NFE) AF: 0.121 AC: 8239 AN: 68022

Other (OTH) AF: 0.225 AC: 476 AN: 2112

Alfa AF: 0.185 Hom.: 1149

Bravo AF: 0.256

Asia WGS AF: 0.276 AC: 963 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.76
CADD	Benign	5.5
DANN	Benign	0.87
PhyloP100		-1.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs7170682; hg19: chr15-39876412; COSMIC: COSV52950077; COSMIC: COSV52950077;