rs77357454

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001851.6(COL9A1):c.1066-36C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0584 in 1,572,138 control chromosomes in the GnomAD database, including 3,107 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.045 ( 243 hom., cov: 32)

Exomes 𝑓: 0.060 ( 2864 hom. )

Consequence

COL9A1
NM_001851.6 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 0.354

Publications

5 publications found

Variant links:

Genes affected

COL9A1 (HGNC:2217): (collagen type IX alpha 1 chain) This gene encodes one of the three alpha chains of type IX collagen, which is a minor (5-20%) collagen component of hyaline cartilage. Type IX collagen is usually found in tissues containing type II collagen, a fibrillar collagen. Studies in knockout mice have shown that synthesis of the alpha 1 chain is essential for assembly of type IX collagen molecules, a heterotrimeric molecule, and that lack of type IX collagen is associated with early onset osteoarthritis. Mutations in this gene are associated with osteoarthritis in humans, with multiple epiphyseal dysplasia, 6, a form of chondrodysplasia, and with Stickler syndrome, a disease characterized by ophthalmic, orofacial, articular, and auditory defects. Two transcript variants that encode different isoforms have been identified for this gene. [provided by RefSeq, Jul 2008]

COL9A1 Gene-Disease associations (from GenCC):

epiphyseal dysplasia, multiple, 6
Inheritance: AD, AR, Unknown Classification: DEFINITIVE, LIMITED Submitted by: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)
Stickler syndrome, type 4
Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Ambry Genetics, G2P, Genomics England PanelApp, PanelApp Australia, Labcorp Genetics (formerly Invitae)
multiple epiphyseal dysplasia due to collagen 9 anomaly
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
autosomal recessive Stickler syndrome
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
Stickler syndrome
Inheritance: AR Classification: LIMITED Submitted by: ClinGen

COL9A1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.85).

BP6

Variant 6-70272124-G-T is Benign according to our data. Variant chr6-70272124-G-T is described in ClinVar as [Benign]. Clinvar id is 258336.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0686 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL9A1	NM_001851.6 link	c.1066-36C>A		intron_variant	Intron 12 of 37	ENST00000357250.11	NP_001842.3	P20849-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL9A1	ENST00000357250.11 link	c.1066-36C>A		intron_variant	Intron 12 of 37	1	NM_001851.6	ENSP00000349790.6		P20849-1

Frequencies

GnomAD3 genomes

AF:

0.0453

AC:

6875

AN:

151910

Hom.:

243

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0116

Gnomad AMI

AF:

0.0789

Gnomad AMR

AF:

0.0323

Gnomad ASJ

AF:

0.0542

Gnomad EAS

AF:

0.00521

Gnomad SAS

AF:

0.0357

Gnomad FIN

AF:

0.0556

Gnomad MID

AF:

0.0285

Gnomad NFE

AF:

0.0702

Gnomad OTH

AF:

0.0364

GnomAD2 exomes

AF:

0.0472

AC:

11402

AN:

241596

AF XY:

0.0480

show subpopulations

Gnomad AFR exome

AF:

0.0104

Gnomad AMR exome

AF:

0.0228

Gnomad ASJ exome

AF:

0.0512

Gnomad EAS exome

AF:

0.00404

Gnomad FIN exome

AF:

0.0620

Gnomad NFE exome

AF:

0.0675

Gnomad OTH exome

AF:

0.0494

GnomAD4 exome

AF:

0.0598

AC:

84935

AN:

1420108

Hom.:

2864

Cov.:

AF XY:

0.0596

AC XY:

42205

AN XY:

708212

show subpopulations

African (AFR)

AF:

0.00939

AC:

301

AN:

32054

American (AMR)

AF:

0.0237

AC:

1042

AN:

44050

Ashkenazi Jewish (ASJ)

AF:

0.0530

AC:

1360

AN:

25646

East Asian (EAS)

AF:

0.00198

AC:

AN:

38882

South Asian (SAS)

AF:

0.0339

AC:

2865

AN:

84488

European-Finnish (FIN)

AF:

0.0652

AC:

3433

AN:

52624

Middle Eastern (MID)

AF:

0.0269

AC:

151

AN:

5608

European-Non Finnish (NFE)

AF:

0.0674

AC:

72694

AN:

1078036

Other (OTH)

AF:

0.0513

AC:

3012

AN:

58720

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.467

Heterozygous variant carriers

3295

6590

9885

13180

16475

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

2578

5156

7734

10312

12890

<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:

0.0452

AC:

6876

AN:

152030

Hom.:

243

Cov.:

AF XY:

0.0437

AC XY:

3247

AN XY:

74310

show subpopulations

African (AFR)

AF:

0.0115

AC:

479

AN:

41504

American (AMR)

AF:

0.0322

AC:

492

AN:

15262

Ashkenazi Jewish (ASJ)

AF:

0.0542

AC:

188

AN:

3468

East Asian (EAS)

AF:

0.00522

AC:

AN:

5168

South Asian (SAS)

AF:

0.0363

AC:

174

AN:

4792

European-Finnish (FIN)

AF:

0.0556

AC:

588

AN:

10570

Middle Eastern (MID)

AF:

0.0238

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0702

AC:

4773

AN:

67948

Other (OTH)

AF:

0.0360

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

338

676

1014

1352

1690

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

168

252

336

420

<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:

0.0613

Hom.:

107

Bravo

AF:

0.0399

Asia WGS

AF:

0.0190

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:1

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:1

Jun 14, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.85

CADD

Benign

2.1

(source)

DANN

Benign

0.32

PhyloP100

0.35

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over