NM_003246.4:c.1939C>G

Variant names:

• chr15-39589817-C-G
• rs143907582
• NM_003246.4:c.1939C>G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_003246.4(THBS1):​c.1939C>G​(p.Arg647Gly) variant causes a missense change. The variant allele was found at a frequency of 0.000000685 in 1,459,172 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: THBS1 NM_003246.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.15

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]

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

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.756

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
THBS1	NM_003246.4	c.1939C>G	p.Arg647Gly	missense_variant	Exon 13 of 22	ENST00000260356.6	NP_003237.2
THBS1	XM_047432980.1	c.1939C>G	p.Arg647Gly	missense_variant	Exon 13 of 22		XP_047288936.1
THBS1	XM_011521971.3	c.1765C>G	p.Arg589Gly	missense_variant	Exon 12 of 21		XP_011520273.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
THBS1	ENST00000260356.6	c.1939C>G	p.Arg647Gly	missense_variant	Exon 13 of 22	1	NM_003246.4	ENSP00000260356.5
THBS1	ENST00000490247.1	n.405C>G		non_coding_transcript_exon_variant	Exon 3 of 3	2
FSIP1	ENST00000642527.1	n.*215-1243G>C		intron_variant	Intron 3 of 3			ENSP00000496642.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1459172 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 725734

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000756

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.35
BayesDel_addAF	Pathogenic	0.22	D
BayesDel_noAF	Uncertain	0.080
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Benign	0.34	T
Eigen	Uncertain	0.51
Eigen_PC	Uncertain	0.59
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Uncertain	0.95	D
M_CAP	Benign	0.078	D
MetaRNN	Pathogenic	0.76	D
MetaSVM	Uncertain	-0.16	T
MutationAssessor	Benign	1.3	L
PrimateAI	Uncertain	0.71	T
PROVEAN	Benign	-1.9	N
REVEL	Uncertain	0.43
Sift	Benign	0.39	T
Sift4G	Benign	0.35	T
Polyphen		1.0	D
Vest4		0.85
MutPred		0.34		Loss of solvent accessibility (P = 0.0092);
MVP		0.81
MPC		0.62
ClinPred		0.89	D
GERP RS		5.8
Varity_R		0.16
gMVP		0.86

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

Publications

LitVar

Other links and lift over

dbSNP: rs143907582; hg19: chr15-39882018;