Variant 9-92474742-C-CTCATCATCA details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BS1_SupportingBS2

The NM_017680.6(ASPN):c.147_155dupTGATGATGA(p.Asp49_Asp51dup) variant causes a disruptive inframe insertion change. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.027 ( 63 hom., cov: 0)

Exomes 𝑓: 0.022 ( 250 hom. )

Failed GnomAD Quality Control

Consequence

ASPN
NM_017680.6 disruptive_inframe_insertion

Scores

Not classified

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.52

Variant links:

Genes affected

ASPN (HGNC:14872): (asporin) This gene encodes a cartilage extracellular protein that is member of the small leucine-rich proteoglycan family. The encoded protein may regulate chondrogenesis by inhibiting transforming growth factor-beta 1-induced gene expression in cartilage. This protein also binds collagen and calcium and may induce collagen mineralization. Polymorphisms in the aspartic acid repeat region of this gene are associated with a susceptibility to osteoarthritis, and also with intervertebral disc disease. Alternative splicing of this gene results in multiple transcript variants.[provided by RefSeq, Jul 2014]

ASPN links:

CENPP (HGNC:32933): (centromere protein P) CENPP is a subunit of a CENPH (MIM 605607)-CENPI (MIM 300065)-associated centromeric complex that targets CENPA (MIM 117139) to centromeres and is required for proper kinetochore function and mitotic progression (Okada et al., 2006 [PubMed 16622420]).[supplied by OMIM, Mar 2008]

CENPP links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -5 ACMG points.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0269 (3971/147656) while in subpopulation AFR AF= 0.0438 (1736/39654). AF 95% confidence interval is 0.0421. There are 63 homozygotes in gnomad4. There are 1914 alleles in male gnomad4 subpopulation. Median coverage is 0. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

BS2

High Homozygotes in GnomAd4 at 63 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CENPP	NM_001012267.3 link	c.564+94919_564+94927dupATCATCATC		intron_variant	Intron 5 of 7	ENST00000375587.8	NP_001012267.1	Q6IPU0-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ASPN	ENST00000375544.7 link	c.147_155dupTGATGATGA	p.Asp49_Asp51dup	disruptive_inframe_insertion	Exon 2 of 8	1		ENSP00000364694.3		Q9BXN1
CENPP	ENST00000375587.8 link	c.564+94919_564+94927dupATCATCATC		intron_variant	Intron 5 of 7	1	NM_001012267.3	ENSP00000364737.3		Q6IPU0-1

Frequencies

GnomAD3 genomes

AF:

0.0269

AC:

3965

AN:

147550

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0436

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0229

Gnomad ASJ

AF:

0.0224

Gnomad EAS

AF:

0.0140

Gnomad SAS

AF:

0.0366

Gnomad FIN

AF:

0.0125

Gnomad MID

AF:

0.0677

Gnomad NFE

AF:

0.0204

Gnomad OTH

AF:

0.0369

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.0221

AC:

30603

AN:

1386552

Hom.:

250

Cov.:

AF XY:

0.0225

AC XY:

15526

AN XY:

690438

show subpopulations

Gnomad4 AFR exome

AF:

0.0481

Gnomad4 AMR exome

AF:

0.0165

Gnomad4 ASJ exome

AF:

0.0227

Gnomad4 EAS exome

AF:

0.0244

Gnomad4 SAS exome

AF:

0.0350

Gnomad4 FIN exome

AF:

0.0145

Gnomad4 NFE exome

AF:

0.0206

Gnomad4 OTH exome

AF:

0.0244

GnomAD4 genome

AF:

0.0269

AC:

3971

AN:

147656

Hom.:

Cov.:

AF XY:

0.0267

AC XY:

1914

AN XY:

71780

show subpopulations

Gnomad4 AFR

AF:

0.0438

Gnomad4 AMR

AF:

0.0229

Gnomad4 ASJ

AF:

0.0224

Gnomad4 EAS

AF:

0.0140

Gnomad4 SAS

AF:

0.0357

Gnomad4 FIN

AF:

0.0125

Gnomad4 NFE

AF:

0.0204

Gnomad4 OTH

AF:

0.0360

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Jun 22, 2023

In-frame duplication of 3 Aspartate residues, which results in an allele with 16 Aspartate residues, or a D16 allele; Significantly over-represented in a study of Han Chinese patients with ankylosing spondylitis (Liu et al., 2010); Reported in 5.8% (43/740) alleles of patients with developmental hip dysplasia in the Han Chinese population, but also seen in 4.4% (39/890) alleles of control samples, which was not a statistically significant difference (Shi et al., 2011); This variant is associated with the following publications: (PMID: 15640800, 21329514, 20144272) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over