6-70234762-A-G

Variant names:

• chr6-70234762-A-G
• rs12191701
• NM_001851.6:c.2259+32T>C

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.2259+32T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.451 in 1,612,902 control chromosomes in the GnomAD database, including 176,376 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.36 (12012 hom., cov: 32)
  • Exomes 𝑓: 0.46 (164364 hom.)
• Consequence: COL9A1 NM_001851.6 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.556
• Publications: 6 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

ENSG00000253809 (HGNC:):

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 6-70234762-A-G is Benign according to our data. Variant chr6-70234762-A-G is described in ClinVar as Benign. ClinVar VariationId is 258357.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.501 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL9A1	NM_001851.6	c.2259+32T>C		intron_variant	Intron 34 of 37	ENST00000357250.11	NP_001842.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL9A1	ENST00000357250.11	c.2259+32T>C		intron_variant	Intron 34 of 37	1	NM_001851.6	ENSP00000349790.6

Frequencies

GnomAD3 genomes AF: 0.360 AC: 54784 AN: 151992 Hom.: 12009 Cov.: 32

Gnomad AFR AF: 0.152

Gnomad AMI AF: 0.434

Gnomad AMR AF: 0.294

Gnomad ASJ AF: 0.559

Gnomad EAS AF: 0.0381

Gnomad SAS AF: 0.281

Gnomad FIN AF: 0.461

Gnomad MID AF: 0.401

Gnomad NFE AF: 0.505

Gnomad OTH AF: 0.373

GnomAD2 exomes AF: 0.377 AC: 94028 AN: 249132 AF XY: 0.388

Gnomad AFR exome AF: 0.145

Gnomad AMR exome AF: 0.210

Gnomad ASJ exome AF: 0.571

Gnomad EAS exome AF: 0.0367

Gnomad FIN exome AF: 0.457

Gnomad NFE exome AF: 0.504

Gnomad OTH exome AF: 0.415

GnomAD4 exome AF: 0.460 AC: 672478 AN: 1460792 Hom.: 164364 Cov.: 45 AF XY: 0.457 AC XY: 332434 AN XY: 726634

African (AFR) AF: 0.143 AC: 4772 AN: 33474

American (AMR) AF: 0.220 AC: 9819 AN: 44650

Ashkenazi Jewish (ASJ) AF: 0.563 AC: 14699 AN: 26126

East Asian (EAS) AF: 0.0351 AC: 1394 AN: 39676

South Asian (SAS) AF: 0.305 AC: 26270 AN: 86200

European-Finnish (FIN) AF: 0.469 AC: 25029 AN: 53356

Middle Eastern (MID) AF: 0.403 AC: 2319 AN: 5752

European-Non Finnish (NFE) AF: 0.506 AC: 562284 AN: 1111232

Other (OTH) AF: 0.429 AC: 25892 AN: 60326

GnomAD4 genome AF: 0.360 AC: 54778 AN: 152110 Hom.: 12012 Cov.: 32 AF XY: 0.354 AC XY: 26329 AN XY: 74352

African (AFR) AF: 0.151 AC: 6283 AN: 41504

American (AMR) AF: 0.293 AC: 4485 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.559 AC: 1939 AN: 3468

East Asian (EAS) AF: 0.0380 AC: 197 AN: 5184

South Asian (SAS) AF: 0.282 AC: 1358 AN: 4822

European-Finnish (FIN) AF: 0.461 AC: 4876 AN: 10570

Middle Eastern (MID) AF: 0.397 AC: 116 AN: 292

European-Non Finnish (NFE) AF: 0.505 AC: 34349 AN: 67954

Other (OTH) AF: 0.369 AC: 779 AN: 2110

Alfa AF: 0.461 Hom.: 28488

Bravo AF: 0.339

Asia WGS AF: 0.144 AC: 504 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Epiphyseal dysplasia, multiple, 6 Benign:1

Jul 30, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1

Jun 23, 2018

GeneDx

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	-0.83
CADD	Benign	3.9
DANN	Benign	0.62
PhyloP100		-0.56
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: rs12191701; hg19: chr6-70944465; COSMIC: COSV107346962; COSMIC: COSV107346962;