Genetic Variant COL9A1:c.2034+19T>G (chr6-70241400-A-C) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001851.6(COL9A1):c.2034+19T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00138 in 1,601,332 control chromosomes in the GnomAD database, including 23 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0068 ( 13 hom., cov: 32)

Exomes 𝑓: 0.00080 ( 10 hom. )

Consequence

COL9A1
NM_001851.6 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 0.908

Publications

6 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:

ENSG00000253809 (HGNC:):

ENSG00000253809 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=-0.82).

BP6

Variant 6-70241400-A-C is Benign according to our data. Variant chr6-70241400-A-C is described in ClinVar as Benign. ClinVar VariationId is 258355.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00685 (1043/152274) while in subpopulation AFR AF = 0.0232 (963/41560). AF 95% confidence interval is 0.022. There are 13 homozygotes in GnomAd4. There are 492 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 13 AR,AD,Unknown gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001851.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
COL9A1	NM_001851.6	MANE Select	c.2034+19T>G	intron	N/A	NP_001842.3
COL9A1	NM_001377289.1		c.1335+19T>G	intron	N/A	NP_001364218.1
COL9A1	NM_078485.4		c.1305+19T>G	intron	N/A	NP_511040.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
COL9A1	ENST00000357250.11	TSL:1 MANE Select	c.2034+19T>G	intron	N/A	ENSP00000349790.6
COL9A1	ENST00000320755.12	TSL:1	c.1305+19T>G	intron	N/A	ENSP00000315252.7
COL9A1	ENST00000683980.2		c.1335+19T>G	intron	N/A	ENSP00000506990.1

Frequencies

GnomAD3 genomes

AF:

0.00689

AC:

1048

AN:

152156

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0233

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00353

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.0158

Gnomad NFE

AF:

0.000206

Gnomad OTH

AF:

0.00431

GnomAD2 exomes

AF:

0.00191

AC:

480

AN:

251336

AF XY:

0.00129

show subpopulations

Gnomad AFR exome

AF:

0.0245

Gnomad AMR exome

AF:

0.00150

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000167

Gnomad OTH exome

AF:

0.00163

GnomAD4 exome

AF:

0.000803

AC:

1163

AN:

1449058

Hom.:

Cov.:

AF XY:

0.000711

AC XY:

513

AN XY:

721852

show subpopulations

African (AFR)

AF:

0.0247

AC:

820

AN:

33264

American (AMR)

AF:

0.00168

AC:

AN:

44714

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26028

East Asian (EAS)

AF:

0.00

AC:

AN:

39662

South Asian (SAS)

AF:

0.0000465

AC:

AN:

86098

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53402

Middle Eastern (MID)

AF:

0.00366

AC:

AN:

5744

European-Non Finnish (NFE)

AF:

0.000108

AC:

119

AN:

1100172

Other (OTH)

AF:

0.00207

AC:

124

AN:

59974

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.470

Heterozygous variant carriers

107

160

214

267

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

120

150

<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:

0.00685

AC:

1043

AN:

152274

Hom.:

Cov.:

AF XY:

0.00661

AC XY:

492

AN XY:

74452

show subpopulations

African (AFR)

AF:

0.0232

AC:

963

AN:

41560

American (AMR)

AF:

0.00353

AC:

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5190

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10600

Middle Eastern (MID)

AF:

0.0136

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000191

AC:

AN:

68014

Other (OTH)

AF:

0.00427

AC:

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

100

151

201

251

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:

0.000211

Hom.:

454

ClinVar

ClinVar submissions as Germline

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (2)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.82

CADD

Benign

4.0

(source)

DANN

Benign

0.59

PhyloP100

0.91

Mutation Taster

=100/0

polymorphism

(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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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