15-39588604-G-A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PP2 PP3 BS2

The NM_003246.4(THBS1):c.1550G>A(p.Arg517His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000161 in 1,610,688 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00016 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00016 (0 hom.)
• Consequence: THBS1 NM_003246.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 10.0

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

Verdict is Likely_benign. Variant got -2 ACMG points.

• PP2: Missense variant where missense usually causes diseases, THBS1
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.746
• BS2: High AC in GnomAd at 25 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
THBS1	NM_003246.4	c.1550G>A	p.Arg517His	missense_variant	10/22	ENST00000260356.6
THBS1	XM_047432980.1	c.1550G>A	p.Arg517His	missense_variant	10/22
THBS1	XM_011521971.3	c.1472-355G>A		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
THBS1	ENST00000260356.6	c.1550G>A	p.Arg517His	missense_variant	10/22	1	NM_003246.4	P1
THBS1-AS1	ENST00000616754.1	n.279C>T		non_coding_transcript_exon_variant	1/1
THBS1	ENST00000497720.1	n.346G>A		non_coding_transcript_exon_variant	3/3	2
FSIP1	ENST00000642527.1	c.*215-30C>T		intron_variant, NMD_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.000164 AC: 25 AN: 152126 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000386

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000338

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000202 AC: 50 AN: 247916 Hom.: 0 AF XY: 0.000224 AC XY: 30 AN XY: 133954

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000294

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000717

Gnomad SAS exome AF: 0.0000336

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000302

Gnomad OTH exome AF: 0.000166

GnomAD4 exome AF: 0.000160 AC: 234 AN: 1458562 Hom.: 0 Cov.: 31 AF XY: 0.000170 AC XY: 123 AN XY: 725476

Gnomad4 AFR exome AF: 0.0000603

Gnomad4 AMR exome AF: 0.0000227

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000302

Gnomad4 SAS exome AF: 0.0000117

Gnomad4 FIN exome AF: 0.0000375

Gnomad4 NFE exome AF: 0.000188

Gnomad4 OTH exome AF: 0.0000996

GnomAD4 genome AF: 0.000164 AC: 25 AN: 152126 Hom.: 0 Cov.: 33 AF XY: 0.000121 AC XY: 9 AN XY: 74302

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000386

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000338

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000271 Hom.: 0

Bravo AF: 0.000136

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.000231 AC: 28

EpiCase AF: 0.000218

EpiControl AF: 0.000178

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 06, 2021

The c.1550G>A (p.R517H) alteration is located in exon 10 (coding exon 9) of the THBS1 gene. This alteration results from a G to A substitution at nucleotide position 1550, causing the arginine (R) at amino acid position 517 to be replaced by a histidine (H). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.094
BayesDel_addAF	Uncertain	0.043	T
BayesDel_noAF	Pathogenic	0.20
Cadd	Pathogenic	32
Dann	Pathogenic	1.0
DEOGEN2	Uncertain	0.47	T
Eigen	Pathogenic	1.2
Eigen_PC	Pathogenic	1.1
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Benign	0.065	D
MetaRNN	Pathogenic	0.75	D
MetaSVM	Uncertain	0.60	D
MutationAssessor	Pathogenic	4.5	H
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.53	T
PROVEAN	Uncertain	-2.5	D
REVEL	Uncertain	0.60
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0020	D
Polyphen		1.0	D
Vest4		0.94
MVP		0.88
MPC		1.4
ClinPred		0.59	D
GERP RS		5.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.68
gMVP		0.79

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs201837685; hg19: chr15-39880805; COSMIC: COSV105018436; COSMIC: COSV105018436;