NM_003247.5:c.1478-8C>T

Variant names:

• chr6-169234915-G-A
• rs9406328
• NM_003247.5:c.1478-8C>T

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BA1

The NM_003247.5(THBS2):​c.1478-8C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.361 in 1,598,004 control chromosomes in the GnomAD database, including 107,259 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign,risk factor (no stars).

• Frequency:
  • Genomes: 𝑓 0.32 (8435 hom., cov: 33)
  • Exomes 𝑓: 0.37 (98824 hom.)
• Consequence: THBS2 NM_003247.5 splice_region, intron
• Scores: Splicing: ADA: 0.00002656
• Clinical Significance: Benign; risk factor no assertion criteria provided B:1 O:1
• Conservation: PhyloP100: 0.523
• Publications: 21 publications found

Genes affected

THBS2 (HGNC:11786): (thrombospondin 2) The protein encoded by this gene belongs to the thrombospondin family. It is a disulfide-linked homotrimeric glycoprotein that mediates cell-to-cell and cell-to-matrix interactions. This protein has been shown to function as a potent inhibitor of tumor growth and angiogenesis. Studies of the mouse counterpart suggest that this protein may modulate the cell surface properties of mesenchymal cells and be involved in cell adhesion and migration. [provided by RefSeq, Jul 2008]

THBS2-AS1 (HGNC:56059): (THBS2 antisense RNA 1)

ACMG classification

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 6-169234915-G-A is Benign according to our data. Variant chr6-169234915-G-A is described in ClinVar as Benign|risk_factor. ClinVar VariationId is 12713.Status of the report is no_assertion_criteria_provided, 0 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.481 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003247.5. 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
	THBS2	NM_003247.5	MANE Select	c.1478-8C>T		splice_region intron	N/A	NP_003238.2
	THBS2	NM_001381939.1		c.1478-1898C>T		intron	N/A	NP_001368868.1	A0A7I2V585
	THBS2	NM_001381942.1		c.1247-8C>T		splice_region intron	N/A	NP_001368871.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	THBS2	ENST00000617924.6	TSL:1 MANE Select	c.1478-8C>T		splice_region intron	N/A	ENSP00000482784.1	P35442
	THBS2	ENST00000366787.7	TSL:1	c.1478-8C>T		splice_region intron	N/A	ENSP00000355751.3	P35442
	THBS2	ENST00000649844.1		c.1493-8C>T		splice_region intron	N/A	ENSP00000497834.1	A0A3B3ITK0

Frequencies

GnomAD3 genomes AF: 0.318 AC: 48335 AN: 151908 Hom.: 8442 Cov.: 33

Gnomad AFR AF: 0.193

Gnomad AMI AF: 0.263

Gnomad AMR AF: 0.397

Gnomad ASJ AF: 0.343

Gnomad EAS AF: 0.497

Gnomad SAS AF: 0.450

Gnomad FIN AF: 0.281

Gnomad MID AF: 0.282

Gnomad NFE AF: 0.359

Gnomad OTH AF: 0.316

GnomAD2 exomes AF: 0.369 AC: 88720 AN: 240332 AF XY: 0.372

Gnomad AFR exome AF: 0.190

Gnomad AMR exome AF: 0.433

Gnomad ASJ exome AF: 0.357

Gnomad EAS exome AF: 0.491

Gnomad FIN exome AF: 0.291

Gnomad NFE exome AF: 0.351

Gnomad OTH exome AF: 0.354

GnomAD4 exome AF: 0.365 AC: 528130 AN: 1445978 Hom.: 98824 Cov.: 36 AF XY: 0.368 AC XY: 264145 AN XY: 717432

African (AFR) AF: 0.184 AC: 6089 AN: 33140

American (AMR) AF: 0.428 AC: 18581 AN: 43450

Ashkenazi Jewish (ASJ) AF: 0.360 AC: 9218 AN: 25640

East Asian (EAS) AF: 0.541 AC: 21276 AN: 39344

South Asian (SAS) AF: 0.450 AC: 38287 AN: 85024

European-Finnish (FIN) AF: 0.289 AC: 14939 AN: 51696

Middle Eastern (MID) AF: 0.290 AC: 1545 AN: 5320

European-Non Finnish (NFE) AF: 0.360 AC: 396805 AN: 1102732

Other (OTH) AF: 0.359 AC: 21390 AN: 59632

GnomAD4 genome AF: 0.318 AC: 48334 AN: 152026 Hom.: 8435 Cov.: 33 AF XY: 0.319 AC XY: 23689 AN XY: 74308

African (AFR) AF: 0.193 AC: 7998 AN: 41474

American (AMR) AF: 0.397 AC: 6063 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.343 AC: 1192 AN: 3472

East Asian (EAS) AF: 0.497 AC: 2546 AN: 5122

South Asian (SAS) AF: 0.449 AC: 2162 AN: 4812

European-Finnish (FIN) AF: 0.281 AC: 2979 AN: 10608

Middle Eastern (MID) AF: 0.276 AC: 81 AN: 294

European-Non Finnish (NFE) AF: 0.359 AC: 24408 AN: 67944

Other (OTH) AF: 0.316 AC: 665 AN: 2106

Alfa AF: 0.338 Hom.: 3266

Bravo AF: 0.318

Asia WGS AF: 0.439 AC: 1528 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign; risk factor

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	-	1	THBS2-related disorder (1)
-	-	-	Lumbar disk herniation, susceptibility to (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	3.0
DANN	Benign	0.67
PhyloP100		0.52
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000027
dbscSNV1_RF	Benign	0.018
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: rs9406328; hg19: chr6-169635010; COSMIC: COSV64678874;