rs6935778

Positions:

• chr6-70269621-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001851.6(COL9A1):​c.1230+12T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.173 in 1,569,944 control chromosomes in the GnomAD database, including 25,837 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.15 (2025 hom., cov: 32)
  • Exomes 𝑓: 0.18 (23812 hom.)
• Consequence: COL9A1 NM_001851.6 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.257

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.57).
• BP6: Variant 6-70269621-A-G is Benign according to our data. Variant chr6-70269621-A-G is described in ClinVar as [Benign]. Clinvar id is 258341.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-70269621-A-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.201 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COL9A1	NM_001851.6	c.1230+12T>C		intron_variant		ENST00000357250.11	NP_001842.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COL9A1	ENST00000357250.11	c.1230+12T>C		intron_variant		1	NM_001851.6	ENSP00000349790	P1

Frequencies

GnomAD3 genomes AF: 0.155 AC: 23515 AN: 152108 Hom.: 2026 Cov.: 32

Gnomad AFR AF: 0.101

Gnomad AMI AF: 0.121

Gnomad AMR AF: 0.129

Gnomad ASJ AF: 0.207

Gnomad EAS AF: 0.00135

Gnomad SAS AF: 0.0708

Gnomad FIN AF: 0.185

Gnomad MID AF: 0.203

Gnomad NFE AF: 0.204

Gnomad OTH AF: 0.154

GnomAD3 exomes AF: 0.149 AC: 37200 AN: 250410 Hom.: 3372 AF XY: 0.151 AC XY: 20454 AN XY: 135448

Gnomad AFR exome AF: 0.0994

Gnomad AMR exome AF: 0.0877

Gnomad ASJ exome AF: 0.201

Gnomad EAS exome AF: 0.000435

Gnomad SAS exome AF: 0.0760

Gnomad FIN exome AF: 0.178

Gnomad NFE exome AF: 0.207

Gnomad OTH exome AF: 0.166

GnomAD4 exome AF: 0.176 AC: 248821 AN: 1417718 Hom.: 23812 Cov.: 26 AF XY: 0.174 AC XY: 122970 AN XY: 708098

Gnomad4 AFR exome AF: 0.0986

Gnomad4 AMR exome AF: 0.0921

Gnomad4 ASJ exome AF: 0.199

Gnomad4 EAS exome AF: 0.000734

Gnomad4 SAS exome AF: 0.0784

Gnomad4 FIN exome AF: 0.184

Gnomad4 NFE exome AF: 0.195

Gnomad4 OTH exome AF: 0.164

GnomAD4 genome AF: 0.154 AC: 23516 AN: 152226 Hom.: 2025 Cov.: 32 AF XY: 0.152 AC XY: 11339 AN XY: 74422

Gnomad4 AFR AF: 0.100

Gnomad4 AMR AF: 0.129

Gnomad4 ASJ AF: 0.207

Gnomad4 EAS AF: 0.00135

Gnomad4 SAS AF: 0.0711

Gnomad4 FIN AF: 0.185

Gnomad4 NFE AF: 0.204

Gnomad4 OTH AF: 0.152

Alfa AF: 0.175 Hom.: 643

Bravo AF: 0.149

Asia WGS AF: 0.0390 AC: 138 AN: 3474

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 05, 2016	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. -

Epiphyseal dysplasia, multiple, 6 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 30, 2021

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.57
CADD	Benign	12
DANN	Benign	0.85

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

LitVar

Other links and lift over

dbSNP: rs6935778; hg19: chr6-70979324;