9-92466381-C-T

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The ENST00000375544.7(ASPN):c.578G>A(p.Gly193Glu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00912 in 1,605,986 control chromosomes in the GnomAD database, including 93 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0075 (11 hom., cov: 32)
  • Exomes 𝑓: 0.0093 (82 hom.)
• Consequence: ASPN ENST00000375544.7 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 7.57

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 Benign. Variant got -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.019685864).
• BP6: Variant 9-92466381-C-T is Benign according to our data. Variant chr9-92466381-C-T is described in ClinVar as [Benign]. Clinvar id is 3041357.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Homozygotes in GnomAd at 11 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ASPN	NM_017680.6	c.578G>A	p.Gly193Glu	missense_variant	4/8	ENST00000710274.1
ASPN	NM_001193335.3	c.578G>A	p.Gly193Glu	missense_variant	4/6
CENPP	NM_001012267.3	c.564+86522C>T		intron_variant		ENST00000375587.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ASPN	ENST00000375544.7	c.578G>A	p.Gly193Glu	missense_variant	4/8	1		P1
CENPP	ENST00000375587.8	c.564+86522C>T		intron_variant		1	NM_001012267.3	P1
ASPN	ENST00000375543.2	c.578G>A	p.Gly193Glu	missense_variant	4/6	2
ASPN	ENST00000650794.1	c.387+4288G>A		intron_variant, NMD_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.00748 AC: 1138 AN: 152074 Hom.: 11 Cov.: 32

Gnomad AFR AF: 0.00227

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.00511

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00560

Gnomad FIN AF: 0.00963

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0119

Gnomad OTH AF: 0.00813

GnomAD3 exomes AF: 0.00740 AC: 1856 AN: 250764 Hom.: 11 AF XY: 0.00798 AC XY: 1082 AN XY: 135548

Gnomad AFR exome AF: 0.00172

Gnomad AMR exome AF: 0.00382

Gnomad ASJ exome AF: 0.000696

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00451

Gnomad FIN exome AF: 0.00939

Gnomad NFE exome AF: 0.0116

Gnomad OTH exome AF: 0.00557

GnomAD4 exome AF: 0.00929 AC: 13513 AN: 1453794 Hom.: 82 Cov.: 30 AF XY: 0.00921 AC XY: 6663 AN XY: 723758

Gnomad4 AFR exome AF: 0.00138

Gnomad4 AMR exome AF: 0.00385

Gnomad4 ASJ exome AF: 0.00123

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00450

Gnomad4 FIN exome AF: 0.0106

Gnomad4 NFE exome AF: 0.0107

Gnomad4 OTH exome AF: 0.00706

GnomAD4 genome AF: 0.00746 AC: 1136 AN: 152192 Hom.: 11 Cov.: 32 AF XY: 0.00742 AC XY: 552 AN XY: 74406

Gnomad4 AFR AF: 0.00226

Gnomad4 AMR AF: 0.00504

Gnomad4 ASJ AF: 0.00144

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00560

Gnomad4 FIN AF: 0.00963

Gnomad4 NFE AF: 0.0119

Gnomad4 OTH AF: 0.00805

Alfa AF: 0.0103 Hom.: 18

Bravo AF: 0.00667

TwinsUK AF: 0.00674 AC: 25

ALSPAC AF: 0.0101 AC: 39

ESP6500AA AF: 0.00136 AC: 6

ESP6500EA AF: 0.0101 AC: 87

ExAC AF: 0.00735 AC: 892

Asia WGS AF: 0.00144 AC: 5 AN: 3478

EpiCase AF: 0.0101

EpiControl AF: 0.0113

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

ASPN-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

May 08, 2019

This variant is classified as 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
AlphaMissense	Benign	0.28
BayesDel_addAF	Benign	-0.015	T
BayesDel_noAF	Pathogenic	0.22
Cadd	Pathogenic	27
Dann	Uncertain	1.0
DEOGEN2	Benign	0.22	T;.
Eigen	Pathogenic	0.87
Eigen_PC	Pathogenic	0.86
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.90	D;D
MetaRNN	Benign	0.020	T;T
MetaSVM	Uncertain	-0.072	T
MutationAssessor	Uncertain	2.4	M;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.72	T
PROVEAN	Pathogenic	-6.0	D;D
REVEL	Uncertain	0.63
Sift	Uncertain	0.0010	D;D
Sift4G	Uncertain	0.0040	D;D
Polyphen		1.0	D;P
Vest4		0.90
MVP		0.97
MPC		0.86
ClinPred		0.052	T
GERP RS		5.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.9
Varity_R		0.87

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs41278695; hg19: chr9-95228663;