6-70253453-T-G

Variant names:

• chr6-70253453-T-G
• rs701690
• NM_001851.6:c.1720-24A>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.1720-24A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.404 in 1,568,784 control chromosomes in the GnomAD database, including 130,053 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.42 (13531 hom., cov: 32)
  • Exomes 𝑓: 0.40 (116522 hom.)
• Consequence: COL9A1 NM_001851.6 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.722
• Publications: 11 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

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BP6: Variant 6-70253453-T-G is Benign according to our data. Variant chr6-70253453-T-G is described in ClinVar as Benign. ClinVar VariationId is 258350.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.483 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL9A1	NM_001851.6	c.1720-24A>C		intron_variant	Intron 25 of 37	ENST00000357250.11	NP_001842.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL9A1	ENST00000357250.11	c.1720-24A>C		intron_variant	Intron 25 of 37	1	NM_001851.6	ENSP00000349790.6

Frequencies

GnomAD3 genomes AF: 0.418 AC: 63507 AN: 151906 Hom.: 13527 Cov.: 32

Gnomad AFR AF: 0.489

Gnomad AMI AF: 0.360

Gnomad AMR AF: 0.339

Gnomad ASJ AF: 0.431

Gnomad EAS AF: 0.284

Gnomad SAS AF: 0.293

Gnomad FIN AF: 0.395

Gnomad MID AF: 0.427

Gnomad NFE AF: 0.416

Gnomad OTH AF: 0.399

GnomAD2 exomes AF: 0.382 AC: 95799 AN: 250958 AF XY: 0.381

Gnomad AFR exome AF: 0.496

Gnomad AMR exome AF: 0.301

Gnomad ASJ exome AF: 0.436

Gnomad EAS exome AF: 0.283

Gnomad FIN exome AF: 0.386

Gnomad NFE exome AF: 0.420

Gnomad OTH exome AF: 0.397

GnomAD4 exome AF: 0.402 AC: 569817 AN: 1416760 Hom.: 116522 Cov.: 25 AF XY: 0.399 AC XY: 282337 AN XY: 707572

African (AFR) AF: 0.495 AC: 16005 AN: 32318

American (AMR) AF: 0.304 AC: 13545 AN: 44574

Ashkenazi Jewish (ASJ) AF: 0.429 AC: 11082 AN: 25814

East Asian (EAS) AF: 0.271 AC: 10688 AN: 39450

South Asian (SAS) AF: 0.308 AC: 26070 AN: 84754

European-Finnish (FIN) AF: 0.394 AC: 20955 AN: 53196

Middle Eastern (MID) AF: 0.409 AC: 2323 AN: 5678

European-Non Finnish (NFE) AF: 0.415 AC: 445425 AN: 1072176

Other (OTH) AF: 0.403 AC: 23724 AN: 58800

GnomAD4 genome AF: 0.418 AC: 63550 AN: 152024 Hom.: 13531 Cov.: 32 AF XY: 0.412 AC XY: 30635 AN XY: 74314

African (AFR) AF: 0.489 AC: 20256 AN: 41442

American (AMR) AF: 0.338 AC: 5174 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.431 AC: 1493 AN: 3468

East Asian (EAS) AF: 0.282 AC: 1461 AN: 5176

South Asian (SAS) AF: 0.294 AC: 1415 AN: 4820

European-Finnish (FIN) AF: 0.395 AC: 4161 AN: 10544

Middle Eastern (MID) AF: 0.429 AC: 126 AN: 294

European-Non Finnish (NFE) AF: 0.416 AC: 28296 AN: 67974

Other (OTH) AF: 0.398 AC: 840 AN: 2108

Alfa AF: 0.376 Hom.: 3325

Bravo AF: 0.421

Asia WGS AF: 0.302 AC: 1052 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 26, 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	-0.92
CADD	Benign	1.2
DANN	Benign	0.44
PhyloP100		-0.72
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: rs701690; hg19: chr6-70963156; COSMIC: COSV57892909;