6-70279648-CAAAAAAAAAAAA-CAAAAAAAAA

Variant names:

• chr6-70279648-CAAA-C
• rs57993118
• NM_001851.6:c.975+1161_975+1163delTTT

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS1

The NM_001851.6(COL9A1):​c.975+1161_975+1163delTTT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0012 in 58,244 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0010 (0 hom., cov: 20)
  • Exomes 𝑓: 0.015 (0 hom.)
• Consequence: COL9A1 NM_001851.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0380
• Publications: 0 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):

• Stickler syndrome, type 4

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Genomics England PanelApp, ClinGen, Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
• epiphyseal dysplasia, multiple, 6

  Inheritance: Unknown, AD, AR Classification: DEFINITIVE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
• 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 -4 ACMG points.

• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.00104 (60/57570) while in subpopulation EAS AF = 0.00609 (13/2136). AF 95% confidence interval is 0.0036. There are 0 homozygotes in GnomAd4. There are 30 alleles in the male GnomAd4 subpopulation. Median coverage is 20. This position passed quality control check.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001851.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL9A1	NM_001851.6	MANE Select	c.975+1161_975+1163delTTT		intron	N/A	NP_001842.3
	COL9A1	NM_001377289.1		c.246+1161_246+1163delTTT		intron	N/A	NP_001364218.1	A0A804HIB6
	COL9A1	NM_078485.4		c.246+1161_246+1163delTTT		intron	N/A	NP_511040.2	P20849-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL9A1	ENST00000357250.11	TSL:1 MANE Select	c.975+1161_975+1163delTTT		intron	N/A	ENSP00000349790.6	P20849-1
	COL9A1	ENST00000320755.12	TSL:1	c.246+1161_246+1163delTTT		intron	N/A	ENSP00000315252.7	P20849-2
	COL9A1	ENST00000683980.2		c.246+1161_246+1163delTTT		intron	N/A	ENSP00000506990.1	A0A804HIB6

Frequencies

GnomAD3 genomes AF: 0.00104 AC: 60 AN: 57542 Hom.: 0 Cov.: 20

Gnomad AFR AF: 0.00171

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00150

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00607

Gnomad SAS AF: 0.000763

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000383

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0148 AC: 10 AN: 674 Hom.: 0 AF XY: 0.00811 AC XY: 3 AN XY: 370

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

African (AFR) AF: 0.0667 AC: 2 AN: 30

American (AMR) AF: 0.00 AC: 0 AN: 24

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 32

East Asian (EAS) AF: 0.0161 AC: 1 AN: 62

South Asian (SAS) AF: 0.00 AC: 0 AN: 6

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 28

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4

European-Non Finnish (NFE) AF: 0.0114 AC: 5 AN: 440

Other (OTH) AF: 0.0417 AC: 2 AN: 48

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.0258005), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.00104 AC: 60 AN: 57570 Hom.: 0 Cov.: 20 AF XY: 0.00114 AC XY: 30 AN XY: 26414

African (AFR) AF: 0.00170 AC: 28 AN: 16430

American (AMR) AF: 0.00150 AC: 7 AN: 4680

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 1486

East Asian (EAS) AF: 0.00609 AC: 13 AN: 2136

South Asian (SAS) AF: 0.000766 AC: 1 AN: 1306

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 1580

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 72

European-Non Finnish (NFE) AF: 0.000383 AC: 11 AN: 28726

Other (OTH) AF: 0.00 AC: 0 AN: 716

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.038

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: rs57993118; hg19: chr6-70989351;