rs6910140

Variant names:

• chr6-70234554-T-C
• rs6910140
• NM_001851.6:c.2299A>G

Your query was ambiguous. Multiple possible variants found:

• chr6-70234554-T-C
• chr6-70234554-T-G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001851.6(COL9A1):​c.2299A>G​(p.Met767Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0228 in 1,614,108 control chromosomes in the GnomAD database, including 1,093 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.045 (278 hom., cov: 32)
  • Exomes 𝑓: 0.021 (815 hom.)
• Consequence: COL9A1 NM_001851.6 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 1.81
• Publications: 16 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.002387613).
• BP6: Variant 6-70234554-T-C is Benign according to our data. Variant chr6-70234554-T-C is described in ClinVar as Benign. ClinVar VariationId is 258358.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.102 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.2299A>G	p.Met767Val	missense	Exon 35 of 38	NP_001842.3
	COL9A1	NM_001377289.1		c.1600A>G	p.Met534Val	missense	Exon 30 of 33	NP_001364218.1
	COL9A1	NM_078485.4		c.1570A>G	p.Met524Val	missense	Exon 29 of 32	NP_511040.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL9A1	ENST00000357250.11	TSL:1 MANE Select	c.2299A>G	p.Met767Val	missense	Exon 35 of 38	ENSP00000349790.6
	COL9A1	ENST00000320755.12	TSL:1	c.1570A>G	p.Met524Val	missense	Exon 29 of 32	ENSP00000315252.7
	COL9A1	ENST00000683980.2		c.1600A>G	p.Met534Val	missense	Exon 30 of 33	ENSP00000506990.1

Frequencies

GnomAD3 genomes AF: 0.0449 AC: 6828 AN: 152160 Hom.: 278 Cov.: 32

Gnomad AFR AF: 0.0976

Gnomad AMI AF: 0.00219

Gnomad AMR AF: 0.0605

Gnomad ASJ AF: 0.0542

Gnomad EAS AF: 0.109

Gnomad SAS AF: 0.0176

Gnomad FIN AF: 0.00593

Gnomad MID AF: 0.0316

Gnomad NFE AF: 0.0127

Gnomad OTH AF: 0.0388

GnomAD2 exomes AF: 0.0394 AC: 9914 AN: 251372 AF XY: 0.0338

Gnomad AFR exome AF: 0.101

Gnomad AMR exome AF: 0.108

Gnomad ASJ exome AF: 0.0478

Gnomad EAS exome AF: 0.107

Gnomad FIN exome AF: 0.00693

Gnomad NFE exome AF: 0.0121

Gnomad OTH exome AF: 0.0346

GnomAD4 exome AF: 0.0205 AC: 30018 AN: 1461830 Hom.: 815 Cov.: 32 AF XY: 0.0195 AC XY: 14157 AN XY: 727222

African (AFR) AF: 0.101 AC: 3368 AN: 33478

American (AMR) AF: 0.103 AC: 4597 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.0486 AC: 1269 AN: 26136

East Asian (EAS) AF: 0.0960 AC: 3810 AN: 39692

South Asian (SAS) AF: 0.0118 AC: 1017 AN: 86258

European-Finnish (FIN) AF: 0.00683 AC: 365 AN: 53414

Middle Eastern (MID) AF: 0.0180 AC: 104 AN: 5768

European-Non Finnish (NFE) AF: 0.0122 AC: 13609 AN: 1111968

Other (OTH) AF: 0.0311 AC: 1879 AN: 60396

GnomAD4 genome AF: 0.0449 AC: 6838 AN: 152278 Hom.: 278 Cov.: 32 AF XY: 0.0453 AC XY: 3375 AN XY: 74450

African (AFR) AF: 0.0976 AC: 4054 AN: 41546

American (AMR) AF: 0.0606 AC: 928 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.0542 AC: 188 AN: 3468

East Asian (EAS) AF: 0.109 AC: 565 AN: 5178

South Asian (SAS) AF: 0.0174 AC: 84 AN: 4834

European-Finnish (FIN) AF: 0.00593 AC: 63 AN: 10616

Middle Eastern (MID) AF: 0.0306 AC: 9 AN: 294

European-Non Finnish (NFE) AF: 0.0127 AC: 864 AN: 68014

Other (OTH) AF: 0.0384 AC: 81 AN: 2112

Alfa AF: 0.0266 Hom.: 215

Bravo AF: 0.0533

TwinsUK AF: 0.0111 AC: 41

ALSPAC AF: 0.0132 AC: 51

ESP6500AA AF: 0.0951 AC: 419

ESP6500EA AF: 0.0148 AC: 127

ExAC AF: 0.0375 AC: 4553

Asia WGS AF: 0.0650 AC: 225 AN: 3478

EpiCase AF: 0.0115

EpiControl AF: 0.0121

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	3	not provided (3)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.20
CADD	Benign	17
DANN	Benign	0.93
DEOGEN2	Benign	0.14	T
Eigen	Benign	-0.20
Eigen_PC	Benign	-0.051
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.88	D
MetaRNN	Benign	0.0024	T
MetaSVM	Uncertain	-0.21	T
MutationAssessor	Benign	1.6	L
PhyloP100		1.8
PrimateAI	Benign	0.47	T
PROVEAN	Benign	-1.5	N
REVEL	Uncertain	0.33
Sift	Benign	0.27	T
Sift4G	Benign	0.19	T
Polyphen		0.25	B
Vest4		0.12
MPC		0.081
ClinPred		0.0031	T
GERP RS		3.3
Varity_R		0.32
gMVP		0.60
Mutation Taster		=74/26	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs6910140; hg19: chr6-70944257; COSMIC: COSV107346959; COSMIC: COSV107346959;