15-39589264-C-A

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 1P and 4B. PP2 BP4_Strong

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
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.207

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 Likely_benign. Variant got -3 ACMG points.

• PP2: Missense variant where missense usually causes diseases, THBS1
• BP4: Computational evidence support a benign effect (MetaRNN=0.05736202).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
THBS1	NM_003246.4	c.1836C>A	p.Asp612Glu	missense_variant	12/22	ENST00000260356.6
THBS1	XM_047432980.1	c.1836C>A	p.Asp612Glu	missense_variant	12/22
THBS1	XM_011521971.3	c.1662C>A	p.Asp554Glu	missense_variant	11/21

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
THBS1	ENST00000260356.6	c.1836C>A	p.Asp612Glu	missense_variant	12/22	1	NM_003246.4	P1
THBS1	ENST00000490247.1	n.302C>A		non_coding_transcript_exon_variant	2/3	2
FSIP1	ENST00000642527.1	c.*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

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

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 04, 2022

The 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;