9-92474742-CTCATCATCATCATCATCATCATCA-CTCATCATCATCATCATCATCATCATCATCATCA

Variant names:

• chr9-92474742-C-CTCATCATCA
• rs3078372
• NM_017680.6:c.147_155dupTGATGATGA

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP3 BS1_Supporting BS2

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
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.52
• Publications: 9 publications found

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

Our verdict: Likely_benign. The variant received -6 ACMG points.

• BP3: Nonframeshift variant in repetitive region in NM_017680.6
• 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 the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAd4 at 63 gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_017680.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ASPN	NM_017680.6	MANE Select	c.147_155dupTGATGATGA	p.Asp49_Asp51dup	disruptive_inframe_insertion	Exon 2 of 8	NP_060150.4
	CENPP	NM_001012267.3	MANE Select	c.564+94919_564+94927dupATCATCATC		intron	N/A	NP_001012267.1	Q6IPU0-1
	ASPN	NM_001193335.3		c.147_155dupTGATGATGA	p.Asp49_Asp51dup	disruptive_inframe_insertion	Exon 2 of 6	NP_001180264.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ASPN	ENST00000375544.7	TSL:1	c.147_155dupTGATGATGA	p.Asp49_Asp51dup	disruptive_inframe_insertion	Exon 2 of 8	ENSP00000364694.3	Q9BXN1
	CENPP	ENST00000375587.8	TSL:1 MANE Select	c.564+94919_564+94927dupATCATCATC		intron	N/A	ENSP00000364737.3	Q6IPU0-1
	ASPN	ENST00000907468.1		c.147_155dupTGATGATGA	p.Asp49_Asp51dup	disruptive_inframe_insertion	Exon 3 of 9	ENSP00000577527.1

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

African (AFR) AF: 0.0481 AC: 1477 AN: 30702

American (AMR) AF: 0.0165 AC: 679 AN: 41064

Ashkenazi Jewish (ASJ) AF: 0.0227 AC: 564 AN: 24898

East Asian (EAS) AF: 0.0244 AC: 919 AN: 37692

South Asian (SAS) AF: 0.0350 AC: 2856 AN: 81692

European-Finnish (FIN) AF: 0.0145 AC: 730 AN: 50512

Middle Eastern (MID) AF: 0.0452 AC: 252 AN: 5574

European-Non Finnish (NFE) AF: 0.0206 AC: 21723 AN: 1056900

Other (OTH) AF: 0.0244 AC: 1403 AN: 57518

GnomAD4 genome AF: 0.0269 AC: 3971 AN: 147656 Hom.: 63 Cov.: 0 AF XY: 0.0267 AC XY: 1914 AN XY: 71780

African (AFR) AF: 0.0438 AC: 1736 AN: 39654

American (AMR) AF: 0.0229 AC: 336 AN: 14686

Ashkenazi Jewish (ASJ) AF: 0.0224 AC: 77 AN: 3430

East Asian (EAS) AF: 0.0140 AC: 70 AN: 4990

South Asian (SAS) AF: 0.0357 AC: 163 AN: 4562

European-Finnish (FIN) AF: 0.0125 AC: 125 AN: 9962

Middle Eastern (MID) AF: 0.0694 AC: 20 AN: 288

European-Non Finnish (NFE) AF: 0.0204 AC: 1371 AN: 67160

Other (OTH) AF: 0.0360 AC: 73 AN: 2026

Alfa AF: 0.0243 Hom.: 224

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		4.5
Mutation Taster		=79/21	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs3078372; hg19: chr9-95237024; COSMIC: COSV65016001;