chr6-70216654-CT-C

Variant names:

• chr6-70216654-CT-C
• rs3215859
• NM_001851.6:c.*242delA

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP6_Moderate

The NM_001851.6(COL9A1):​c.*242delA variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0021 (0 hom., cov: 0)
  • Exomes 𝑓: 0.18 (0 hom.)
• Consequence: COL9A1 NM_001851.6 3_prime_UTR
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -2.00
• Publications: 2 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: Likely_benign. The variant received -2 ACMG points.

• BP6: Variant 6-70216654-CT-C is Benign according to our data. Variant chr6-70216654-CT-C is described in ClinVar as [Likely_benign]. Clinvar id is 1189526.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL9A1	NM_001851.6	c.*242delA		3_prime_UTR_variant	Exon 38 of 38	ENST00000357250.11	NP_001842.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL9A1	ENST00000357250.11	c.*242delA		3_prime_UTR_variant	Exon 38 of 38	1	NM_001851.6	ENSP00000349790.6

Frequencies

GnomAD3 genomes AF: 0.00209 AC: 304 AN: 145542 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.000759

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00129

Gnomad ASJ AF: 0.00176

Gnomad EAS AF: 0.000805

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0106

Gnomad MID AF: 0.00671

Gnomad NFE AF: 0.00213

Gnomad OTH AF: 0.00299

GnomAD4 exome AF: 0.176 AC: 56254 AN: 318856 Hom.: 0 Cov.: 0 AF XY: 0.179 AC XY: 29979 AN XY: 167542

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.181 AC: 1634 AN: 9036

American (AMR) AF: 0.152 AC: 2095 AN: 13748

Ashkenazi Jewish (ASJ) AF: 0.202 AC: 1962 AN: 9714

East Asian (EAS) AF: 0.141 AC: 3014 AN: 21358

South Asian (SAS) AF: 0.213 AC: 7423 AN: 34840

European-Finnish (FIN) AF: 0.154 AC: 2909 AN: 18886

Middle Eastern (MID) AF: 0.200 AC: 283 AN: 1414

European-Non Finnish (NFE) AF: 0.176 AC: 33728 AN: 191754

Other (OTH) AF: 0.177 AC: 3206 AN: 18106

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.00211 AC: 307 AN: 145584 Hom.: 0 Cov.: 0 AF XY: 0.00252 AC XY: 178 AN XY: 70672

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.000833 AC: 33 AN: 39628

American (AMR) AF: 0.00129 AC: 19 AN: 14748

Ashkenazi Jewish (ASJ) AF: 0.00176 AC: 6 AN: 3404

East Asian (EAS) AF: 0.000807 AC: 4 AN: 4956

South Asian (SAS) AF: 0.00 AC: 0 AN: 4522

European-Finnish (FIN) AF: 0.0106 AC: 96 AN: 9040

Middle Eastern (MID) AF: 0.00735 AC: 2 AN: 272

European-Non Finnish (NFE) AF: 0.00213 AC: 141 AN: 66104

Other (OTH) AF: 0.00298 AC: 6 AN: 2016

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 232

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Aug 10, 2019

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		-2.0
Mutation Taster		=100/0	polymorphism

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: rs3215859; hg19: chr6-70926357; COSMIC: COSV57893236; COSMIC: COSV57893236;