6-70216654-C-CTT

Variant names:

• chr6-70216654-C-CTT
• rs3215859
• NM_001851.6:c.*241_*242dupAA

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6_Moderate BA1

The NM_001851.6(COL9A1):​c.*241_*242dupAA variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.086 (719 hom., cov: 0)
  • Exomes 𝑓: 0.039 (37 hom.)
• Consequence: COL9A1 NM_001851.6 3_prime_UTR
• Clinical Significance: 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: Benign. The variant received -10 ACMG points.

• BP6: Variant 6-70216654-C-CTT is Benign according to our data. Variant chr6-70216654-C-CTT is described in ClinVar as [Benign]. Clinvar id is 1259219.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.167 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL9A1	NM_001851.6	c.*241_*242dupAA		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.*241_*242dupAA		3_prime_UTR_variant	Exon 38 of 38	1	NM_001851.6	ENSP00000349790.6

Frequencies

GnomAD3 genomes AF: 0.0863 AC: 12578 AN: 145788 Hom.: 719 Cov.: 0

Gnomad AFR AF: 0.171

Gnomad AMI AF: 0.0201

Gnomad AMR AF: 0.0512

Gnomad ASJ AF: 0.0425

Gnomad EAS AF: 0.00523

Gnomad SAS AF: 0.0523

Gnomad FIN AF: 0.0515

Gnomad MID AF: 0.0201

Gnomad NFE AF: 0.0607

Gnomad OTH AF: 0.0696

GnomAD4 exome AF: 0.0391 AC: 13084 AN: 334820 Hom.: 37 Cov.: 0 AF XY: 0.0384 AC XY: 6753 AN XY: 176066

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

African (AFR) AF: 0.115 AC: 1092 AN: 9456

American (AMR) AF: 0.0308 AC: 443 AN: 14392

Ashkenazi Jewish (ASJ) AF: 0.0273 AC: 281 AN: 10296

East Asian (EAS) AF: 0.00791 AC: 176 AN: 22248

South Asian (SAS) AF: 0.0344 AC: 1289 AN: 37434

European-Finnish (FIN) AF: 0.0388 AC: 759 AN: 19570

Middle Eastern (MID) AF: 0.0280 AC: 41 AN: 1466

European-Non Finnish (NFE) AF: 0.0407 AC: 8178 AN: 201004

Other (OTH) AF: 0.0435 AC: 825 AN: 18954

⚠️ 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: 0.0863 AC: 12580 AN: 145828 Hom.: 719 Cov.: 0 AF XY: 0.0852 AC XY: 6036 AN XY: 70814

African (AFR) AF: 0.171 AC: 6764 AN: 39610

American (AMR) AF: 0.0512 AC: 756 AN: 14776

Ashkenazi Jewish (ASJ) AF: 0.0425 AC: 145 AN: 3408

East Asian (EAS) AF: 0.00524 AC: 26 AN: 4958

South Asian (SAS) AF: 0.0526 AC: 238 AN: 4528

European-Finnish (FIN) AF: 0.0515 AC: 469 AN: 9100

Middle Eastern (MID) AF: 0.0147 AC: 4 AN: 272

European-Non Finnish (NFE) AF: 0.0607 AC: 4020 AN: 66258

Other (OTH) AF: 0.0692 AC: 140 AN: 2024

Alfa AF: 0.0177 Hom.: 232

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Aug 06, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

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

Splicing

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: COSV57880258; COSMIC: COSV57880258;