rs77357454

chr6-70272124-G-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.1066-36C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0584 in 1,572,138 control chromosomes in the GnomAD database, including 3,107 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.045 (243 hom., cov: 32)
  • Exomes 𝑓: 0.060 (2864 hom.)
• Consequence: COL9A1 NM_001851.6 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.354

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=-0.85).
• BP6: Variant 6-70272124-G-T is Benign according to our data. Variant chr6-70272124-G-T is described in ClinVar as [Benign]. Clinvar id is 258336.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0686 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL9A1	NM_001851.6	c.1066-36C>A		intron_variant		ENST00000357250.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL9A1	ENST00000357250.11	c.1066-36C>A		intron_variant		1	NM_001851.6	P1

Frequencies

GnomAD3 genomes AF: 0.0453 AC: 6875 AN: 151910 Hom.: 243 Cov.: 32

Gnomad AFR AF: 0.0116

Gnomad AMI AF: 0.0789

Gnomad AMR AF: 0.0323

Gnomad ASJ AF: 0.0542

Gnomad EAS AF: 0.00521

Gnomad SAS AF: 0.0357

Gnomad FIN AF: 0.0556

Gnomad MID AF: 0.0285

Gnomad NFE AF: 0.0702

Gnomad OTH AF: 0.0364

GnomAD3 exomes AF: 0.0472 AC: 11402 AN: 241596 Hom.: 343 AF XY: 0.0480 AC XY: 6269 AN XY: 130680

Gnomad AFR exome AF: 0.0104

Gnomad AMR exome AF: 0.0228

Gnomad ASJ exome AF: 0.0512

Gnomad EAS exome AF: 0.00404

Gnomad SAS exome AF: 0.0332

Gnomad FIN exome AF: 0.0620

Gnomad NFE exome AF: 0.0675

Gnomad OTH exome AF: 0.0494

GnomAD4 exome AF: 0.0598 AC: 84935 AN: 1420108 Hom.: 2864 Cov.: 26 AF XY: 0.0596 AC XY: 42205 AN XY: 708212

Gnomad4 AFR exome AF: 0.00939

Gnomad4 AMR exome AF: 0.0237

Gnomad4 ASJ exome AF: 0.0530

Gnomad4 EAS exome AF: 0.00198

Gnomad4 SAS exome AF: 0.0339

Gnomad4 FIN exome AF: 0.0652

Gnomad4 NFE exome AF: 0.0674

Gnomad4 OTH exome AF: 0.0513

GnomAD4 genome AF: 0.0452 AC: 6876 AN: 152030 Hom.: 243 Cov.: 32 AF XY: 0.0437 AC XY: 3247 AN XY: 74310

Gnomad4 AFR AF: 0.0115

Gnomad4 AMR AF: 0.0322

Gnomad4 ASJ AF: 0.0542

Gnomad4 EAS AF: 0.00522

Gnomad4 SAS AF: 0.0363

Gnomad4 FIN AF: 0.0556

Gnomad4 NFE AF: 0.0702

Gnomad4 OTH AF: 0.0360

Alfa AF: 0.0626 Hom.: 69

Bravo AF: 0.0399

Asia WGS AF: 0.0190 AC: 67 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

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

-

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 14, 2018

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	-0.85
Cadd	Benign	2.1
Dann	Benign	0.32

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: rs77357454; hg19: chr6-70981827; COSMIC: COSV57878864; COSMIC: COSV57878864;