9-92474742-C-CTCATCATCA

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BS1_Supporting BS2

The NM_001193335.3(ASPN):c.155_156insTGATGATGA(p.Asp49_Asp51dup) variant causes a 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_001193335.3 inframe_insertion
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.52

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]

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]

ACMG classification

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 GnomAd at 64 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ASPN	NM_017680.6	c.155_156insTGATGATGA	p.Asp49_Asp51dup	inframe_insertion	2/8	ENST00000710274.1
ASPN	NM_001193335.3	c.155_156insTGATGATGA	p.Asp49_Asp51dup	inframe_insertion	2/6
CENPP	NM_001012267.3	c.564+94919_564+94927dup		intron_variant		ENST00000375587.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ASPN	ENST00000375544.7	c.155_156insTGATGATGA	p.Asp49_Asp51dup	inframe_insertion	2/8	1		P1
CENPP	ENST00000375587.8	c.564+94919_564+94927dup		intron_variant		1	NM_001012267.3	P1

Frequencies

GnomAD3 genomes AF: 0.0269 AC: 3965 AN: 147550 Hom.: 64 Cov.: 0

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.: 0 AF XY: 0.0225 AC XY: 15526 AN XY: 690438

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.: 63 Cov.: 0 AF XY: 0.0267 AC XY: 1914 AN XY: 71780

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

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

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs3078372; hg19: chr9-95237024;