rs117215769

Variant names:

• chr6-70281377-G-A
• rs117215769
• NM_001851.6:c.876+13C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001851.6(COL9A1):​c.876+13C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0575 in 1,610,872 control chromosomes in the GnomAD database, including 3,111 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.044 (227 hom., cov: 31)
  • Exomes 𝑓: 0.059 (2884 hom.)
• Consequence: COL9A1 NM_001851.6 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.0920
• Publications: 5 publications found

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

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant 6-70281377-G-A is Benign according to our data. Variant chr6-70281377-G-A is described in ClinVar as Benign. ClinVar VariationId is 258361.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0672 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL9A1	NM_001851.6	c.876+13C>T		intron_variant	Intron 8 of 37	ENST00000357250.11	NP_001842.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL9A1	ENST00000357250.11	c.876+13C>T		intron_variant	Intron 8 of 37	1	NM_001851.6	ENSP00000349790.6

Frequencies

GnomAD3 genomes AF: 0.0441 AC: 6684 AN: 151406 Hom.: 227 Cov.: 31

Gnomad AFR AF: 0.0113

Gnomad AMI AF: 0.0725

Gnomad AMR AF: 0.0328

Gnomad ASJ AF: 0.0373

Gnomad EAS AF: 0.00549

Gnomad SAS AF: 0.0337

Gnomad FIN AF: 0.0557

Gnomad MID AF: 0.0191

Gnomad NFE AF: 0.0689

Gnomad OTH AF: 0.0351

GnomAD2 exomes AF: 0.0456 AC: 11418 AN: 250370 AF XY: 0.0465

Gnomad AFR exome AF: 0.0104

Gnomad AMR exome AF: 0.0225

Gnomad ASJ exome AF: 0.0374

Gnomad EAS exome AF: 0.00409

Gnomad FIN exome AF: 0.0624

Gnomad NFE exome AF: 0.0657

Gnomad OTH exome AF: 0.0471

GnomAD4 exome AF: 0.0589 AC: 85890 AN: 1459360 Hom.: 2884 Cov.: 31 AF XY: 0.0586 AC XY: 42516 AN XY: 726072

African (AFR) AF: 0.00897 AC: 300 AN: 33456

American (AMR) AF: 0.0237 AC: 1061 AN: 44684

Ashkenazi Jewish (ASJ) AF: 0.0391 AC: 1021 AN: 26110

East Asian (EAS) AF: 0.00209 AC: 83 AN: 39676

South Asian (SAS) AF: 0.0320 AC: 2758 AN: 86136

European-Finnish (FIN) AF: 0.0648 AC: 3456 AN: 53316

Middle Eastern (MID) AF: 0.0176 AC: 101 AN: 5740

European-Non Finnish (NFE) AF: 0.0668 AC: 74147 AN: 1109976

Other (OTH) AF: 0.0492 AC: 2963 AN: 60266

GnomAD4 genome AF: 0.0441 AC: 6683 AN: 151512 Hom.: 227 Cov.: 31 AF XY: 0.0427 AC XY: 3159 AN XY: 74048

African (AFR) AF: 0.0113 AC: 466 AN: 41298

American (AMR) AF: 0.0328 AC: 500 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.0373 AC: 129 AN: 3462

East Asian (EAS) AF: 0.00550 AC: 28 AN: 5088

South Asian (SAS) AF: 0.0341 AC: 163 AN: 4776

European-Finnish (FIN) AF: 0.0557 AC: 586 AN: 10520

Middle Eastern (MID) AF: 0.0172 AC: 5 AN: 290

European-Non Finnish (NFE) AF: 0.0688 AC: 4667 AN: 67800

Other (OTH) AF: 0.0347 AC: 73 AN: 2104

Alfa AF: 0.0599 Hom.: 81

Bravo AF: 0.0391

Asia WGS AF: 0.0180 AC: 64 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

-

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 05, 2016

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. -

-

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not provided Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	6.5
DANN	Benign	0.51
PhyloP100		-0.092
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs117215769; hg19: chr6-70991080;