6-70279648-CAAAAAAAAAAAA-CAAAAAAA

Variant names:

• chr6-70279648-CAAAAA-C
• rs57993118
• NM_001851.6:c.975+1159_975+1163delTTTTT

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BA1

The NM_001851.6(COL9A1):​c.975+1159_975+1163delTTTTT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0984 in 58,284 control chromosomes in the GnomAD database, including 172 homozygotes. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.098 (170 hom., cov: 20)
  • Exomes 𝑓: 0.11 (2 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: Benign. The variant received -8 ACMG points.

• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.136 is higher than 0.05.

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+1159_975+1163delTTTTT		intron	N/A	NP_001842.3
	COL9A1	NM_001377289.1		c.246+1159_246+1163delTTTTT		intron	N/A	NP_001364218.1	A0A804HIB6
	COL9A1	NM_078485.4		c.246+1159_246+1163delTTTTT		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+1159_975+1163delTTTTT		intron	N/A	ENSP00000349790.6	P20849-1
	COL9A1	ENST00000320755.12	TSL:1	c.246+1159_246+1163delTTTTT		intron	N/A	ENSP00000315252.7	P20849-2
	COL9A1	ENST00000683980.2		c.246+1159_246+1163delTTTTT		intron	N/A	ENSP00000506990.1	A0A804HIB6

Frequencies

GnomAD3 genomes AF: 0.0982 AC: 5654 AN: 57580 Hom.: 169 Cov.: 20

Gnomad AFR AF: 0.0396

Gnomad AMI AF: 0.151

Gnomad AMR AF: 0.0723

Gnomad ASJ AF: 0.113

Gnomad EAS AF: 0.0117

Gnomad SAS AF: 0.0998

Gnomad FIN AF: 0.131

Gnomad MID AF: 0.0921

Gnomad NFE AF: 0.139

Gnomad OTH AF: 0.0899

GnomAD4 exome AF: 0.107 AC: 72 AN: 676 Hom.: 2 AF XY: 0.0968 AC XY: 36 AN XY: 372

African (AFR) AF: 0.133 AC: 4 AN: 30

American (AMR) AF: 0.167 AC: 4 AN: 24

Ashkenazi Jewish (ASJ) AF: 0.125 AC: 4 AN: 32

East Asian (EAS) AF: 0.0323 AC: 2 AN: 62

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

European-Finnish (FIN) AF: 0.107 AC: 3 AN: 28

Middle Eastern (MID) AF: 0.250 AC: 1 AN: 4

European-Non Finnish (NFE) AF: 0.115 AC: 51 AN: 442

Other (OTH) AF: 0.0625 AC: 3 AN: 48

GnomAD4 genome AF: 0.0983 AC: 5663 AN: 57608 Hom.: 170 Cov.: 20 AF XY: 0.0947 AC XY: 2505 AN XY: 26446

African (AFR) AF: 0.0401 AC: 659 AN: 16450

American (AMR) AF: 0.0722 AC: 339 AN: 4694

Ashkenazi Jewish (ASJ) AF: 0.113 AC: 167 AN: 1484

East Asian (EAS) AF: 0.0117 AC: 25 AN: 2140

South Asian (SAS) AF: 0.101 AC: 132 AN: 1308

European-Finnish (FIN) AF: 0.131 AC: 207 AN: 1580

Middle Eastern (MID) AF: 0.0833 AC: 6 AN: 72

European-Non Finnish (NFE) AF: 0.139 AC: 3998 AN: 28724

Other (OTH) AF: 0.0891 AC: 64 AN: 718

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
Mutation Taster		=100/0	polymorphism

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs57993118; hg19: chr6-70989351;