chr6-70255042-G-T

Variant names:

• chr6-70255042-G-T
• rs13219431
• NM_001851.6:c.1612-26C>A

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.1612-26C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.164 in 1,613,340 control chromosomes in the GnomAD database, including 24,224 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.13 (1628 hom., cov: 32)
  • Exomes 𝑓: 0.17 (22596 hom.)
• Consequence: COL9A1 NM_001851.6 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 1.17
• Publications: 5 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=-0.74).
• BP6: Variant 6-70255042-G-T is Benign according to our data. Variant chr6-70255042-G-T is described in ClinVar as Benign. ClinVar VariationId is 258346.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.188 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL9A1	NM_001851.6	c.1612-26C>A		intron_variant	Intron 23 of 37	ENST00000357250.11	NP_001842.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL9A1	ENST00000357250.11	c.1612-26C>A		intron_variant	Intron 23 of 37	1	NM_001851.6	ENSP00000349790.6

Frequencies

GnomAD3 genomes AF: 0.127 AC: 19241 AN: 151994 Hom.: 1626 Cov.: 32

Gnomad AFR AF: 0.0319

Gnomad AMI AF: 0.121

Gnomad AMR AF: 0.107

Gnomad ASJ AF: 0.188

Gnomad EAS AF: 0.00116

Gnomad SAS AF: 0.0539

Gnomad FIN AF: 0.185

Gnomad MID AF: 0.133

Gnomad NFE AF: 0.191

Gnomad OTH AF: 0.130

GnomAD2 exomes AF: 0.133 AC: 33400 AN: 251352 AF XY: 0.136

Gnomad AFR exome AF: 0.0282

Gnomad AMR exome AF: 0.0748

Gnomad ASJ exome AF: 0.185

Gnomad EAS exome AF: 0.000326

Gnomad FIN exome AF: 0.178

Gnomad NFE exome AF: 0.193

Gnomad OTH exome AF: 0.150

GnomAD4 exome AF: 0.168 AC: 244811 AN: 1461228 Hom.: 22596 Cov.: 32 AF XY: 0.165 AC XY: 120048 AN XY: 726972

African (AFR) AF: 0.0245 AC: 820 AN: 33478

American (AMR) AF: 0.0778 AC: 3478 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.184 AC: 4798 AN: 26134

East Asian (EAS) AF: 0.000378 AC: 15 AN: 39700

South Asian (SAS) AF: 0.0602 AC: 5193 AN: 86248

European-Finnish (FIN) AF: 0.184 AC: 9819 AN: 53416

Middle Eastern (MID) AF: 0.112 AC: 648 AN: 5762

European-Non Finnish (NFE) AF: 0.190 AC: 210989 AN: 1111388

Other (OTH) AF: 0.150 AC: 9051 AN: 60378

GnomAD4 genome AF: 0.126 AC: 19239 AN: 152112 Hom.: 1628 Cov.: 32 AF XY: 0.125 AC XY: 9324 AN XY: 74378

African (AFR) AF: 0.0319 AC: 1322 AN: 41500

American (AMR) AF: 0.107 AC: 1629 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.188 AC: 651 AN: 3470

East Asian (EAS) AF: 0.00116 AC: 6 AN: 5182

South Asian (SAS) AF: 0.0543 AC: 262 AN: 4822

European-Finnish (FIN) AF: 0.185 AC: 1956 AN: 10552

Middle Eastern (MID) AF: 0.139 AC: 41 AN: 294

European-Non Finnish (NFE) AF: 0.191 AC: 12991 AN: 67982

Other (OTH) AF: 0.128 AC: 271 AN: 2114

Alfa AF: 0.123 Hom.: 357

Bravo AF: 0.117

Asia WGS AF: 0.0260 AC: 92 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	-0.74
CADD	Benign	9.4
DANN	Benign	0.75
PhyloP100		1.2
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: rs13219431; hg19: chr6-70964745;