6-169225232-A-G

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM2 PP2 PP3_Strong PP5_Moderate

The NM_003247.5(THBS2):c.2686T>C(p.Cys896Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,744 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: THBS2 NM_003247.5 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 8.68

Genes affected

THBS2 (HGNC:11786): (thrombospondin 2) The protein encoded by this gene belongs to the thrombospondin family. It is a disulfide-linked homotrimeric glycoprotein that mediates cell-to-cell and cell-to-matrix interactions. This protein has been shown to function as a potent inhibitor of tumor growth and angiogenesis. Studies of the mouse counterpart suggest that this protein may modulate the cell surface properties of mesenchymal cells and be involved in cell adhesion and migration. [provided by RefSeq, Jul 2008]

THBS2-AS1 (HGNC:56059): (THBS2 antisense RNA 1)

ACMG classification

Verdict is Likely_pathogenic. Variant got 9 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, THBS2
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.941
• PP5: Variant 6-169225232-A-G is Pathogenic according to our data. Variant chr6-169225232-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 3062024.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
THBS2	NM_003247.5	c.2686T>C	p.Cys896Arg	missense_variant	17/22	ENST00000617924.6
THBS2-AS1	NR_134621.1	n.681+10745A>G		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
THBS2	ENST00000617924.6	c.2686T>C	p.Cys896Arg	missense_variant	17/22	1	NM_003247.5	P4
THBS2-AS1	ENST00000660724.1	n.639+10745A>G		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461744 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727158

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: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Ehlers-Danlos syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

in vivo;research

The Morris Kahn Laboratory of Human Genetics, Ben-Gurion University of the Negev

Mar 08, 2024

A heterozygous NM_003247.5:c.2686T>C, p.Cys896Arg variant was identified in three female patients exhibiting a novel form of Ehlers-Danlos Syndrome (EDS) characterized by hypermobility, frequent joint dislocations, atrophic scarring, prolonged bleeding times, and age-related aortic dilatation and rupture. Normal results were observed in coagulation tests, platelet counts, and function. The reticular dermis showed highly disorganized collagen fibers, and transmission electron microscopy (TEM) revealed abnormally shaped fibroblasts and endothelial cells, along with a high volume and irregularly shaped extracellular matrix substances, especially surrounding blood vessels. CRISPR/Cas9 knock-in mice replicated these phenotypes, demonstrating hypermobility, prolonged bleeding times, and similar histological features in analyses conducted with both light microscopy and TEM (Noam Hadar et al., 2024). Furthermore, Thbs2-null mice previously produced also exhibited a similar phenotype (Themis R. Kyriakides et al., 1998). Consequently, this variant has been classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.57	D
BayesDel_noAF	Pathogenic	0.58
Cadd	Uncertain	24
Dann	Uncertain	0.98
DEOGEN2	Pathogenic	0.80	D;.;D
Eigen	Uncertain	0.64
Eigen_PC	Uncertain	0.53
FATHMM_MKL	Uncertain	0.95	D
M_CAP	Pathogenic	0.77	D
MetaRNN	Pathogenic	0.94	D;D;D
MetaSVM	Pathogenic	0.88	D
MutationAssessor	Pathogenic	3.6	H;.;H
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.77	T
PROVEAN	Pathogenic	-11	D;.;.
REVEL	Pathogenic	0.78
Sift	Uncertain	0.0020	D;.;.
Sift4G	Uncertain	0.0050	D;.;D
Polyphen		0.91	P;.;P
Vest4		0.97
MutPred		0.56		Gain of solvent accessibility (P = 0.0584);.;Gain of solvent accessibility (P = 0.0584);
MVP		0.99
MPC		1.7
ClinPred		0.96	D
GERP RS		5.0
Varity_R		0.89
gMVP		0.94

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: chr6-169625327;