rs633762

chr6-70255422-A-Cchr6-70255422-A-Gchr6-70255422-A-T

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.1504-32T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.79 in 1,596,956 control chromosomes in the GnomAD database, including 501,288 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.84 (54117 hom., cov: 32)
  • Exomes 𝑓: 0.79 (447171 hom.)
• Consequence: COL9A1 NM_001851.6 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.130

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=-0.93).
• BP6: Variant 6-70255422-A-C is Benign according to our data. Variant chr6-70255422-A-C is described in ClinVar as [Benign]. Clinvar id is 258344.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.951 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL9A1	NM_001851.6	c.1504-32T>G		intron_variant		ENST00000357250.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL9A1	ENST00000357250.11	c.1504-32T>G		intron_variant		1	NM_001851.6	P1

Frequencies

GnomAD3 genomes AF: 0.838 AC: 127544 AN: 152130 Hom.: 54044 Cov.: 32

Gnomad AFR AF: 0.959

Gnomad AMI AF: 0.759

Gnomad AMR AF: 0.849

Gnomad ASJ AF: 0.827

Gnomad EAS AF: 0.930

Gnomad SAS AF: 0.768

Gnomad FIN AF: 0.752

Gnomad MID AF: 0.816

Gnomad NFE AF: 0.777

Gnomad OTH AF: 0.811

GnomAD3 exomes AF: 0.810 AC: 202980 AN: 250650 Hom.: 82805 AF XY: 0.800 AC XY: 108424 AN XY: 135492

Gnomad AFR exome AF: 0.967

Gnomad AMR exome AF: 0.881

Gnomad ASJ exome AF: 0.831

Gnomad EAS exome AF: 0.921

Gnomad SAS exome AF: 0.756

Gnomad FIN exome AF: 0.747

Gnomad NFE exome AF: 0.773

Gnomad OTH exome AF: 0.797

GnomAD4 exome AF: 0.785 AC: 1134633 AN: 1444708 Hom.: 447171 Cov.: 28 AF XY: 0.783 AC XY: 563613 AN XY: 719836

Gnomad4 AFR exome AF: 0.967

Gnomad4 AMR exome AF: 0.876

Gnomad4 ASJ exome AF: 0.824

Gnomad4 EAS exome AF: 0.939

Gnomad4 SAS exome AF: 0.754

Gnomad4 FIN exome AF: 0.748

Gnomad4 NFE exome AF: 0.773

Gnomad4 OTH exome AF: 0.799

GnomAD4 genome AF: 0.839 AC: 127677 AN: 152248 Hom.: 54117 Cov.: 32 AF XY: 0.837 AC XY: 62302 AN XY: 74430

Gnomad4 AFR AF: 0.959

Gnomad4 AMR AF: 0.849

Gnomad4 ASJ AF: 0.827

Gnomad4 EAS AF: 0.930

Gnomad4 SAS AF: 0.769

Gnomad4 FIN AF: 0.752

Gnomad4 NFE AF: 0.777

Gnomad4 OTH AF: 0.814

Alfa AF: 0.781 Hom.: 19493

Bravo AF: 0.852

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

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

GeneDx

Jun 23, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
Cadd	Benign	5.5
Dann	Benign	0.29

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

Other links and lift over

dbSNP: rs633762; hg19: chr6-70965125; COSMIC: COSV57878857; COSMIC: COSV57878857;