15-39589264-C-A

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_003246.4(THBS1):​c.1836C>A​(p.Asp612Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000958 in 1,461,850 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)
Exomes 𝑓: 0.0000096 ( 0 hom. )

Consequence

THBS1
NM_003246.4 missense

Scores

2
17

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.207
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)

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.05736202).
BS2
High AC in GnomAdExome4 at 14 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
THBS1NM_003246.4 linkuse as main transcriptc.1836C>A p.Asp612Glu missense_variant 12/22 ENST00000260356.6
THBS1XM_047432980.1 linkuse as main transcriptc.1836C>A p.Asp612Glu missense_variant 12/22
THBS1XM_011521971.3 linkuse as main transcriptc.1662C>A p.Asp554Glu missense_variant 11/21

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
THBS1ENST00000260356.6 linkuse as main transcriptc.1836C>A p.Asp612Glu missense_variant 12/221 NM_003246.4 P1P07996-1
THBS1ENST00000490247.1 linkuse as main transcriptn.302C>A non_coding_transcript_exon_variant 2/32
FSIP1ENST00000642527.1 linkuse as main transcriptc.*215-690G>T intron_variant, NMD_transcript_variant

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
AF:
0.00000958
AC:
14
AN:
1461850
Hom.:
0
Cov.:
32
AF XY:
0.00000963
AC XY:
7
AN XY:
727226
show subpopulations
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:
0.0000126
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
33

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 GeneticsJan 04, 2022The c.1836C>A (p.D612E) alteration is located in exon 12 (coding exon 11) of the THBS1 gene. This alteration results from a C to A substitution at nucleotide position 1836, causing the aspartic acid (D) at amino acid position 612 to be replaced by a glutamic acid (E). 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
0.11
BayesDel_addAF
Benign
-0.052
T
BayesDel_noAF
Benign
-0.31
CADD
Benign
12
DANN
Benign
0.96
DEOGEN2
Benign
0.21
T
Eigen
Benign
-0.24
Eigen_PC
Benign
-0.20
FATHMM_MKL
Benign
0.15
N
LIST_S2
Benign
0.78
T
M_CAP
Benign
0.0080
T
MetaRNN
Benign
0.057
T
MetaSVM
Benign
-0.99
T
MutationAssessor
Benign
-0.085
N
MutationTaster
Benign
0.80
D
PrimateAI
Uncertain
0.50
T
PROVEAN
Benign
-0.49
N
REVEL
Uncertain
0.31
Sift
Benign
0.75
T
Sift4G
Benign
0.70
T
Polyphen
0.0
B
Vest4
0.16
MutPred
0.25
Gain of solvent accessibility (P = 0.1014);
MVP
0.45
MPC
0.41
ClinPred
0.13
T
GERP RS
2.8
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.031
gMVP
0.40

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: chr15-39881465; COSMIC: COSV99528541; COSMIC: COSV99528541; API