Genetic Variant COL9A1:c.1765-21G>A (chr6-70252336-C-T) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001851.6(COL9A1):c.1765-21G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.192 in 1,609,078 control chromosomes in the GnomAD database, including 30,551 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.18 ( 2581 hom., cov: 32)

Exomes 𝑓: 0.19 ( 27970 hom. )

Consequence

COL9A1
NM_001851.6 intron

Scores

Clinical Significance

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

Conservation

PhyloP100: -0.0310

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 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.82).

BP6

Variant 6-70252336-C-T is Benign according to our data. Variant chr6-70252336-C-T is described in ClinVar as [Benign]. Clinvar id is 258351.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.194 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL9A1	NM_001851.6 link	c.1765-21G>A		intron_variant	Intron 26 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.1765-21G>A		intron_variant	Intron 26 of 37	1	NM_001851.6	ENSP00000349790.6		P20849-1

Frequencies

GnomAD3 genomes

AF:

0.183

AC:

27817

AN:

152054

Hom.:

2578

Cov.:

show subpopulations

Gnomad AFR

AF:

0.181

Gnomad AMI

AF:

0.237

Gnomad AMR

AF:

0.123

Gnomad ASJ

AF:

0.182

Gnomad EAS

AF:

0.173

Gnomad SAS

AF:

0.204

Gnomad FIN

AF:

0.200

Gnomad MID

AF:

0.196

Gnomad NFE

AF:

0.194

Gnomad OTH

AF:

0.178

GnomAD3 exomes

AF:

0.182

AC:

45541

AN:

250830

Hom.:

4311

AF XY:

0.187

AC XY:

25320

AN XY:

135548

show subpopulations

Gnomad AFR exome

AF:

0.180

Gnomad AMR exome

AF:

0.0938

Gnomad ASJ exome

AF:

0.199

Gnomad EAS exome

AF:

0.176

Gnomad SAS exome

AF:

0.218

Gnomad FIN exome

AF:

0.198

Gnomad NFE exome

AF:

0.194

Gnomad OTH exome

AF:

0.188

GnomAD4 exome

AF:

0.193

AC:

280824

AN:

1456906

Hom.:

27970

Cov.:

AF XY:

0.194

AC XY:

140620

AN XY:

725030

show subpopulations

Gnomad4 AFR exome

AF:

0.183

Gnomad4 AMR exome

AF:

0.0979

Gnomad4 ASJ exome

AF:

0.195

Gnomad4 EAS exome

AF:

0.175

Gnomad4 SAS exome

AF:

0.217

Gnomad4 FIN exome

AF:

0.200

Gnomad4 NFE exome

AF:

0.195

Gnomad4 OTH exome

AF:

0.194

GnomAD4 genome

AF:

0.183

AC:

27834

AN:

152172

Hom.:

2581

Cov.:

AF XY:

0.181

AC XY:

13493

AN XY:

74386

show subpopulations

Gnomad4 AFR

AF:

0.181

Gnomad4 AMR

AF:

0.123

Gnomad4 ASJ

AF:

0.182

Gnomad4 EAS

AF:

0.172

Gnomad4 SAS

AF:

0.204

Gnomad4 FIN

AF:

0.200

Gnomad4 NFE

AF:

0.194

Gnomad4 OTH

AF:

0.180

Alfa

AF:

0.183

Hom.:

4341

Bravo

AF:

0.179

Asia WGS

AF:

0.192

AC:

666

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

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

- -

Epiphyseal dysplasia, multiple, 6

Benign:1

Jul 30, 2021

Genome-Nilou Lab

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

-0.82

CADD

Benign

1.7

DANN

Benign

0.52

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over