rs192467838

Variant names:

• chr6-70234894-C-A
• rs192467838
• NM_001851.6:c.2159G>T

Your query was ambiguous. Multiple possible variants found:

• chr6-70234894-C-A
• chr6-70234894-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001851.6(COL9A1):​c.2159G>T​(p.Arg720Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R720Q) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: COL9A1 NM_001851.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.82
• 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):

• 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

ENSG00000253809 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL9A1	NM_001851.6	MANE Select	c.2159G>T	p.Arg720Leu	missense	Exon 34 of 38	NP_001842.3
	COL9A1	NM_001377289.1		c.1460G>T	p.Arg487Leu	missense	Exon 29 of 33	NP_001364218.1
	COL9A1	NM_078485.4		c.1430G>T	p.Arg477Leu	missense	Exon 28 of 32	NP_511040.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL9A1	ENST00000357250.11	TSL:1 MANE Select	c.2159G>T	p.Arg720Leu	missense	Exon 34 of 38	ENSP00000349790.6
	COL9A1	ENST00000320755.12	TSL:1	c.1430G>T	p.Arg477Leu	missense	Exon 28 of 32	ENSP00000315252.7
	COL9A1	ENST00000683980.2		c.1460G>T	p.Arg487Leu	missense	Exon 29 of 33	ENSP00000506990.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 36

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.24
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Uncertain	0.020
CADD	Benign	23
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.72	D
Eigen	Benign	-0.055
Eigen_PC	Benign	0.099
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.81	T
M_CAP	Uncertain	0.12	D
MetaRNN	Uncertain	0.70	D
MetaSVM	Benign	-0.40	T
MutationAssessor	Benign	1.1	L
PhyloP100		7.8
PrimateAI	Uncertain	0.66	T
PROVEAN	Uncertain	-2.9	D
REVEL	Uncertain	0.59
Sift	Uncertain	0.010	D
Sift4G	Benign	0.34	T
Polyphen		0.14	B
Vest4		0.73
MutPred		0.52		Loss of methylation at R720 (P = 0.0176)
MVP		0.88
MPC		0.15
ClinPred		0.97	D
GERP RS		4.9
Varity_R		0.31
gMVP		0.55
Mutation Taster		=31/69	disease causing

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: rs192467838; hg19: chr6-70944597;