9-92470675-T-A

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4_Moderate BP6_Moderate BP7

The ENST00000375544.7(ASPN):c.381A>T(p.Ser127=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000441 in 1,476,116 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00035 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00045 (2 hom.)
• Consequence: ASPN ENST00000375544.7 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.374

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.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.39).
• BP6: Variant 9-92470675-T-A is Benign according to our data. Variant chr9-92470675-T-A is described in ClinVar as [Likely_benign]. Clinvar id is 3051497.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=0.374 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ASPN	NM_017680.6	c.381A>T	p.Ser127=	synonymous_variant	3/8	ENST00000710274.1
ASPN	NM_001193335.3	c.381A>T	p.Ser127=	synonymous_variant	3/6
CENPP	NM_001012267.3	c.564+90816T>A		intron_variant		ENST00000375587.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ASPN	ENST00000375544.7	c.381A>T	p.Ser127=	synonymous_variant	3/8	1		P1
CENPP	ENST00000375587.8	c.564+90816T>A		intron_variant		1	NM_001012267.3	P1

Frequencies

GnomAD3 genomes AF: 0.000361 AC: 55 AN: 152224 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00481

Gnomad SAS AF: 0.000827

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000323

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000724 AC: 166 AN: 229318 Hom.: 1 AF XY: 0.000725 AC XY: 90 AN XY: 124180

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00589

Gnomad SAS exome AF: 0.000927

Gnomad FIN exome AF: 0.000427

Gnomad NFE exome AF: 0.000314

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000451 AC: 597 AN: 1323774 Hom.: 2 Cov.: 21 AF XY: 0.000450 AC XY: 299 AN XY: 664190

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000263

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00889

Gnomad4 SAS exome AF: 0.000898

Gnomad4 FIN exome AF: 0.000360

Gnomad4 NFE exome AF: 0.000144

Gnomad4 OTH exome AF: 0.000341

GnomAD4 genome AF: 0.000354 AC: 54 AN: 152342 Hom.: 0 Cov.: 32 AF XY: 0.000456 AC XY: 34 AN XY: 74486

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00482

Gnomad4 SAS AF: 0.000828

Gnomad4 FIN AF: 0.000188

Gnomad4 NFE AF: 0.000323

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000298 Hom.: 0

Bravo AF: 0.000427

Asia WGS AF: 0.00290 AC: 10 AN: 3466

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

ASPN-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 02, 2020

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.39
Cadd	Benign	9.9
Dann	Benign	0.71

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

LitVar

Other links and lift over

dbSNP: rs144079283; hg19: chr9-95232957;