15-39588617-C-T

Variant names:

• chr15-39588617-C-T
• rs41338344
• NM_003246.4:c.1563C>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.1563C>T​(p.Asn521Asn) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0293 in 1,611,476 control chromosomes in the GnomAD database, including 790 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.022 (68 hom., cov: 32)
  • Exomes 𝑓: 0.030 (722 hom.)
• Consequence: THBS1 NM_003246.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 1.21
• Publications: 6 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-AS1 (HGNC:55224): (THBS1 antisense RNA 1)

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

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.46).
• BP6: Variant 15-39588617-C-T is Benign according to our data. Variant chr15-39588617-C-T is described in ClinVar as Benign. ClinVar VariationId is 403536.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=1.21 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0221 (3369/152276) while in subpopulation NFE AF = 0.0338 (2297/68002). AF 95% confidence interval is 0.0326. There are 68 homozygotes in GnomAd4. There are 1531 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 68 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.1563C>T	p.Asn521Asn	synonymous	Exon 10 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.1563C>T	p.Asn521Asn	synonymous	Exon 10 of 22	ENSP00000260356.5
	THBS1	ENST00000880750.1		c.1563C>T	p.Asn521Asn	synonymous	Exon 11 of 23	ENSP00000550809.1
	THBS1	ENST00000880751.1		c.1563C>T	p.Asn521Asn	synonymous	Exon 11 of 23	ENSP00000550810.1

Frequencies

GnomAD3 genomes AF: 0.0221 AC: 3368 AN: 152158 Hom.: 68 Cov.: 32

Gnomad AFR AF: 0.00577

Gnomad AMI AF: 0.00548

Gnomad AMR AF: 0.0308

Gnomad ASJ AF: 0.0433

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0124

Gnomad FIN AF: 0.00772

Gnomad MID AF: 0.0253

Gnomad NFE AF: 0.0338

Gnomad OTH AF: 0.0267

GnomAD2 exomes AF: 0.0238 AC: 5918 AN: 248838 AF XY: 0.0245

Gnomad AFR exome AF: 0.00599

Gnomad AMR exome AF: 0.0276

Gnomad ASJ exome AF: 0.0379

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00858

Gnomad NFE exome AF: 0.0323

Gnomad OTH exome AF: 0.0319

GnomAD4 exome AF: 0.0301 AC: 43886 AN: 1459200 Hom.: 722 Cov.: 31 AF XY: 0.0300 AC XY: 21764 AN XY: 725820

African (AFR) AF: 0.00544 AC: 181 AN: 33252

American (AMR) AF: 0.0280 AC: 1239 AN: 44302

Ashkenazi Jewish (ASJ) AF: 0.0365 AC: 947 AN: 25938

East Asian (EAS) AF: 0.0000756 AC: 3 AN: 39680

South Asian (SAS) AF: 0.0172 AC: 1471 AN: 85672

European-Finnish (FIN) AF: 0.00978 AC: 522 AN: 53368

Middle Eastern (MID) AF: 0.0286 AC: 164 AN: 5732

European-Non Finnish (NFE) AF: 0.0339 AC: 37617 AN: 1110964

Other (OTH) AF: 0.0289 AC: 1742 AN: 60292

GnomAD4 genome AF: 0.0221 AC: 3369 AN: 152276 Hom.: 68 Cov.: 32 AF XY: 0.0206 AC XY: 1531 AN XY: 74460

African (AFR) AF: 0.00573 AC: 238 AN: 41560

American (AMR) AF: 0.0308 AC: 471 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.0433 AC: 150 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5172

South Asian (SAS) AF: 0.0129 AC: 62 AN: 4824

European-Finnish (FIN) AF: 0.00772 AC: 82 AN: 10622

Middle Eastern (MID) AF: 0.0306 AC: 9 AN: 294

European-Non Finnish (NFE) AF: 0.0338 AC: 2297 AN: 68002

Other (OTH) AF: 0.0260 AC: 55 AN: 2116

Alfa AF: 0.0276 Hom.: 31

Bravo AF: 0.0230

Asia WGS AF: 0.00549 AC: 19 AN: 3478

EpiCase AF: 0.0369

EpiControl AF: 0.0397

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	-0.46
CADD	Benign	18
DANN	Benign	0.81
PhyloP100		1.2
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: rs41338344; hg19: chr15-39880818; COSMIC: COSV52953937; COSMIC: COSV52953937;