chr15-39589946-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_003246.4(THBS1):​c.2068G>C​(p.Gly690Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another nucleotide change resulting in same amino acid change has been previously reported as Uncertain significancein ClinVar.

Frequency

Genomes: not found (cov: 32)

Consequence

THBS1
NM_003246.4 missense

Scores

13
5
1

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 10.0
Variant links:
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)

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.895

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
THBS1NM_003246.4 linkuse as main transcriptc.2068G>C p.Gly690Arg missense_variant 13/22 ENST00000260356.6
THBS1XM_047432980.1 linkuse as main transcriptc.2068G>C p.Gly690Arg missense_variant 13/22
THBS1XM_011521971.3 linkuse as main transcriptc.1894G>C p.Gly632Arg missense_variant 12/21

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
THBS1ENST00000260356.6 linkuse as main transcriptc.2068G>C p.Gly690Arg missense_variant 13/221 NM_003246.4 P1P07996-1
FSIP1ENST00000642527.1 linkuse as main transcriptc.*215-1372C>G intron_variant, NMD_transcript_variant

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
31
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsApr 23, 2024The c.2068G>C (p.G690R) alteration is located in exon 13 (coding exon 12) of the THBS1 gene. This alteration results from a G to C substitution at nucleotide position 2068, causing the glycine (G) at amino acid position 690 to be replaced by an arginine (R). 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
Pathogenic
0.78
BayesDel_addAF
Pathogenic
0.41
D
BayesDel_noAF
Pathogenic
0.35
CADD
Pathogenic
30
DANN
Pathogenic
1.0
DEOGEN2
Uncertain
0.74
D
Eigen
Pathogenic
1.1
Eigen_PC
Pathogenic
1.0
FATHMM_MKL
Uncertain
0.94
D
LIST_S2
Pathogenic
0.99
D
M_CAP
Uncertain
0.13
D
MetaRNN
Pathogenic
0.89
D
MetaSVM
Uncertain
0.54
D
MutationAssessor
Pathogenic
3.0
M
MutationTaster
Benign
1.0
D
PrimateAI
Pathogenic
0.91
D
PROVEAN
Pathogenic
-6.9
D
REVEL
Pathogenic
0.66
Sift
Uncertain
0.0040
D
Sift4G
Pathogenic
0.0010
D
Polyphen
1.0
D
Vest4
0.89
MutPred
0.55
Gain of catalytic residue at G690 (P = 0.075);
MVP
0.88
MPC
1.4
ClinPred
1.0
D
GERP RS
6.0
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.70
gMVP
0.80

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr15-39882147; API