chr9-92466381-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The NM_017680.6(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 (no stars).

Frequency

Genomes: 𝑓 0.0075 ( 11 hom., cov: 32)

Exomes 𝑓: 0.0093 ( 82 hom. )

Consequence

ASPN
NM_017680.6 missense

Scores

Clinical Significance

Benign no assertion criteria provided B:1

Conservation

PhyloP100: 7.57

Publications

6 publications found

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:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -9 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 VariationId is 3041357.Status of the report is no_assertion_criteria_provided, 0 stars.

BS2

High Homozygotes in GnomAd4 at 11 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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ASPN	NM_017680.6	MANE Select	c.578G>A	p.Gly193Glu	missense	Exon 4 of 8	NP_060150.4
CENPP	NM_001012267.3	MANE Select	c.564+86522C>T		intron	N/A	NP_001012267.1	Q6IPU0-1
ASPN	NM_001193335.3		c.578G>A	p.Gly193Glu	missense	Exon 4 of 6	NP_001180264.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ASPN	ENST00000375544.7	TSL:1	c.578G>A	p.Gly193Glu	missense	Exon 4 of 8	ENSP00000364694.3	Q9BXN1
CENPP	ENST00000375587.8	TSL:1 MANE Select	c.564+86522C>T		intron	N/A	ENSP00000364737.3	Q6IPU0-1
ASPN	ENST00000907468.1		c.578G>A	p.Gly193Glu	missense	Exon 5 of 9	ENSP00000577527.1

Frequencies

GnomAD3 genomes

AF:

0.00748

AC:

1138

AN:

152074

Hom.:

Cov.:

show subpopulations

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

GnomAD2 exomes

AF:

0.00740

AC:

1856

AN:

250764

AF XY:

0.00798

show subpopulations

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 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.:

Cov.:

AF XY:

0.00921

AC XY:

6663

AN XY:

723758

show subpopulations

African (AFR)

AF:

0.00138

AC:

AN:

33340

American (AMR)

AF:

0.00385

AC:

172

AN:

44692

Ashkenazi Jewish (ASJ)

AF:

0.00123

AC:

AN:

26086

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39624

South Asian (SAS)

AF:

0.00450

AC:

387

AN:

86036

European-Finnish (FIN)

AF:

0.0106

AC:

563

AN:

53360

Middle Eastern (MID)

AF:

0.00246

AC:

AN:

5686

European-Non Finnish (NFE)

AF:

0.0107

AC:

11874

AN:

1104896

Other (OTH)

AF:

0.00706

AC:

424

AN:

60074

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.467

Heterozygous variant carriers

598

1196

1794

2392

2990

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

406

812

1218

1624

2030

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00746

AC:

1136

AN:

152192

Hom.:

Cov.:

AF XY:

0.00742

AC XY:

552

AN XY:

74406

show subpopulations

African (AFR)

AF:

0.00226

AC:

AN:

41526

American (AMR)

AF:

0.00504

AC:

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.00144

AC:

AN:

3472

East Asian (EAS)

AF:

0.000193

AC:

AN:

5186

South Asian (SAS)

AF:

0.00560

AC:

AN:

4818

European-Finnish (FIN)

AF:

0.00963

AC:

102

AN:

10590

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0119

AC:

812

AN:

68002

Other (OTH)

AF:

0.00805

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

116

173

231

289

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00994

Hom.:

Bravo

AF:

0.00667

TwinsUK

AF:

0.00674

AC:

ALSPAC

AF:

0.0101

AC:

ESP6500AA

AF:

0.00136

AC:

ESP6500EA

AF:

0.0101

AC:

ExAC

AF:

0.00735

AC:

892

Asia WGS

AF:

0.00144

AC:

AN:

3478

EpiCase

AF:

0.0101

EpiControl

AF:

0.0113

ClinVar

ClinVar submissions

Significance:Benign

Revision:no assertion criteria provided

View on ClinVar

Pathogenic

VUS

Benign

Condition

ASPN-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.28

BayesDel_addAF

Benign

-0.015

BayesDel_noAF

Pathogenic

0.22

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.22

Eigen

Pathogenic

0.87

Eigen_PC

Pathogenic

0.86

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.90

MetaRNN

Benign

0.020

MetaSVM

Uncertain

-0.072

MutationAssessor

Uncertain

2.4

PhyloP100

7.6

PrimateAI

Uncertain

0.72

PROVEAN

Pathogenic

-6.0

REVEL

Uncertain

0.63

Sift

Uncertain

0.0010

Sift4G

Uncertain

0.0040

Polyphen

1.0

Vest4

0.90

MVP

0.97

MPC

0.86

ClinPred

0.052

GERP RS

5.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.9

Varity_R

0.87

Mutation Taster

=17/83

disease causing

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over