rs556723130

Variant names:

• chr15-39588648-G-A
• rs556723130
• NM_003246.4:c.1594G>A

Your query was ambiguous. Multiple possible variants found:

• chr15-39588648-G-A
• chr15-39588648-G-C

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Strong BP6_Moderate

The NM_003246.4(THBS1):​c.1594G>A​(p.Val532Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000504 in 1,607,142 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V532A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000085 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000047 (0 hom.)
• Consequence: THBS1 NM_003246.4 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.0370
• Publications: 0 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: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.058271557).
• BP6: Variant 15-39588648-G-A is Benign according to our data. Variant chr15-39588648-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 3456078.Status of the report is criteria_provided_single_submitter, 1 stars.

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.1594G>A	p.Val532Ile	missense	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.1594G>A	p.Val532Ile	missense	Exon 10 of 22	ENSP00000260356.5	P07996-1
	THBS1	ENST00000880750.1		c.1594G>A	p.Val532Ile	missense	Exon 11 of 23	ENSP00000550809.1
	THBS1	ENST00000880751.1		c.1594G>A	p.Val532Ile	missense	Exon 11 of 23	ENSP00000550810.1

Frequencies

GnomAD3 genomes AF: 0.0000854 AC: 13 AN: 152150 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000393

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000451 AC: 11 AN: 244114 AF XY: 0.0000379

Gnomad AFR exome AF: 0.0000621

Gnomad AMR exome AF: 0.000150

Gnomad ASJ exome AF: 0.000105

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000270

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000467 AC: 68 AN: 1454874 Hom.: 0 Cov.: 32 AF XY: 0.0000415 AC XY: 30 AN XY: 723442

African (AFR) AF: 0.0000911 AC: 3 AN: 32920

American (AMR) AF: 0.000184 AC: 8 AN: 43492

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25652

East Asian (EAS) AF: 0.00 AC: 0 AN: 39658

South Asian (SAS) AF: 0.0000354 AC: 3 AN: 84720

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53252

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5654

European-Non Finnish (NFE) AF: 0.0000460 AC: 51 AN: 1109462

Other (OTH) AF: 0.0000499 AC: 3 AN: 60064

GnomAD4 genome AF: 0.0000854 AC: 13 AN: 152268 Hom.: 0 Cov.: 32 AF XY: 0.0000671 AC XY: 5 AN XY: 74466

African (AFR) AF: 0.0000481 AC: 2 AN: 41554

American (AMR) AF: 0.000392 AC: 6 AN: 15304

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10610

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000735 AC: 5 AN: 68008

Other (OTH) AF: 0.00 AC: 0 AN: 2116

Alfa AF: 0.0000455 Hom.: 0

Bravo AF: 0.0000604

ExAC AF: 0.0000412 AC: 5

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.064
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	5.9
DANN	Benign	0.83
DEOGEN2	Benign	0.10	T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.12	N
LIST_S2	Benign	0.65	T
M_CAP	Benign	0.0087	T
MetaRNN	Benign	0.058	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	1.1	L
PhyloP100		0.037
PrimateAI	Benign	0.22	T
PROVEAN	Benign	-0.33	N
REVEL	Benign	0.086
Sift	Benign	0.22	T
Sift4G	Benign	0.52	T
Polyphen		0.0010	B
Vest4		0.066
MutPred		0.58		Gain of methylation at K529 (P = 0.1656)
MVP		0.32
MPC		0.35
ClinPred		0.021	T
GERP RS		-4.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.084
gMVP		0.23
Mutation Taster		=94/6	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: rs556723130; hg19: chr15-39880849;