rs16868869

chr6-70272091-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.1066-3T>C variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0237 in 1,610,200 control chromosomes in the GnomAD database, including 859 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.034 (120 hom., cov: 32)
  • Exomes 𝑓: 0.023 (739 hom.)
• Consequence: COL9A1 NM_001851.6 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.00003366
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.106

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=-0.73).
• BP6: Variant 6-70272091-A-G is Benign according to our data. Variant chr6-70272091-A-G is described in ClinVar as [Benign]. Clinvar id is 258337.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-70272091-A-G is described in Lovd as [Benign]. Variant chr6-70272091-A-G is described in Lovd as [Likely_benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0972 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL9A1	NM_001851.6	c.1066-3T>C		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000357250.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL9A1	ENST00000357250.11	c.1066-3T>C		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_001851.6	P1

Frequencies

GnomAD3 genomes AF: 0.0341 AC: 5183 AN: 152136 Hom.: 118 Cov.: 32

Gnomad AFR AF: 0.0509

Gnomad AMI AF: 0.0132

Gnomad AMR AF: 0.0634

Gnomad ASJ AF: 0.0401

Gnomad EAS AF: 0.105

Gnomad SAS AF: 0.0215

Gnomad FIN AF: 0.00527

Gnomad MID AF: 0.0348

Gnomad NFE AF: 0.0172

Gnomad OTH AF: 0.0335

GnomAD3 exomes AF: 0.0380 AC: 9473 AN: 249450 Hom.: 383 AF XY: 0.0329 AC XY: 4434 AN XY: 134868

Gnomad AFR exome AF: 0.0516

Gnomad AMR exome AF: 0.116

Gnomad ASJ exome AF: 0.0311

Gnomad EAS exome AF: 0.0992

Gnomad SAS exome AF: 0.0125

Gnomad FIN exome AF: 0.00597

Gnomad NFE exome AF: 0.0164

Gnomad OTH exome AF: 0.0308

GnomAD4 exome AF: 0.0226 AC: 32917 AN: 1457946 Hom.: 739 Cov.: 30 AF XY: 0.0216 AC XY: 15644 AN XY: 725532

Gnomad4 AFR exome AF: 0.0512

Gnomad4 AMR exome AF: 0.108

Gnomad4 ASJ exome AF: 0.0326

Gnomad4 EAS exome AF: 0.0866

Gnomad4 SAS exome AF: 0.0126

Gnomad4 FIN exome AF: 0.00663

Gnomad4 NFE exome AF: 0.0170

Gnomad4 OTH exome AF: 0.0282

GnomAD4 genome AF: 0.0340 AC: 5181 AN: 152254 Hom.: 120 Cov.: 32 AF XY: 0.0336 AC XY: 2503 AN XY: 74450

Gnomad4 AFR AF: 0.0508

Gnomad4 AMR AF: 0.0634

Gnomad4 ASJ AF: 0.0401

Gnomad4 EAS AF: 0.104

Gnomad4 SAS AF: 0.0216

Gnomad4 FIN AF: 0.00527

Gnomad4 NFE AF: 0.0172

Gnomad4 OTH AF: 0.0327

Alfa AF: 0.0234 Hom.: 69

Bravo AF: 0.0420

Asia WGS AF: 0.0640 AC: 222 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 11, 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. -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Aug 10, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.73
Cadd	Benign	0.91
Dann	Benign	0.68

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000034
dbscSNV1_RF	Benign	0.0
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

Other links and lift over

dbSNP: rs16868869; hg19: chr6-70981794; COSMIC: COSV57886032; COSMIC: COSV57886032;