chr6-70263290-T-C

Variant names:

• chr6-70263290-T-C
• rs77706858
• NM_001851.6:c.1349A>G
• COL9A1 p.Glu450Gly

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001851.6(COL9A1):​c.1349A>G​(p.Glu450Gly) variant causes a missense change. The variant allele was found at a frequency of 0.00402 in 1,609,246 control chromosomes in the GnomAD database, including 13 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0034 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0041 (13 hom.)
• Consequence: COL9A1 NM_001851.6 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 6.01
• Publications: 14 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, Unknown, AR Classification: DEFINITIVE, LIMITED Submitted by: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics
• Stickler syndrome, type 4

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, Ambry Genetics, Genomics England PanelApp, G2P
• 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.015095472).
• BP6: Variant 6-70263290-T-C is Benign according to our data. Variant chr6-70263290-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 194938.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00336 (512/152180) while in subpopulation NFE AF = 0.00496 (337/67964). AF 95% confidence interval is 0.00452. There are 0 homozygotes in GnomAd4. There are 251 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 13 AR,AD,Unknown gene

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.1349A>G	p.Glu450Gly	missense	Exon 19 of 38	NP_001842.3
	COL9A1	NM_001377289.1		c.620A>G	p.Glu207Gly	missense	Exon 13 of 33	NP_001364218.1	A0A804HIB6
	COL9A1	NM_078485.4		c.620A>G	p.Glu207Gly	missense	Exon 13 of 32	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.1349A>G	p.Glu450Gly	missense	Exon 19 of 38	ENSP00000349790.6	P20849-1
	COL9A1	ENST00000320755.12	TSL:1	c.620A>G	p.Glu207Gly	missense	Exon 13 of 32	ENSP00000315252.7	P20849-2
	COL9A1	ENST00000683980.2		c.620A>G	p.Glu207Gly	missense	Exon 13 of 33	ENSP00000506990.1	A0A804HIB6

Frequencies

GnomAD3 genomes AF: 0.00336 AC: 511 AN: 152062 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000917

Gnomad AMI AF: 0.00219

Gnomad AMR AF: 0.00197

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.00821

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00494

Gnomad OTH AF: 0.00383

GnomAD2 exomes AF: 0.00364 AC: 907 AN: 249288 AF XY: 0.00363

Gnomad AFR exome AF: 0.000873

Gnomad AMR exome AF: 0.000901

Gnomad ASJ exome AF: 0.00149

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00732

Gnomad NFE exome AF: 0.00573

Gnomad OTH exome AF: 0.00427

GnomAD4 exome AF: 0.00409 AC: 5956 AN: 1457066 Hom.: 13 Cov.: 30 AF XY: 0.00402 AC XY: 2910 AN XY: 724594

African (AFR) AF: 0.000750 AC: 25 AN: 33348

American (AMR) AF: 0.00134 AC: 60 AN: 44616

Ashkenazi Jewish (ASJ) AF: 0.00215 AC: 56 AN: 26044

East Asian (EAS) AF: 0.0000253 AC: 1 AN: 39548

South Asian (SAS) AF: 0.000624 AC: 53 AN: 84882

European-Finnish (FIN) AF: 0.00892 AC: 474 AN: 53168

Middle Eastern (MID) AF: 0.000869 AC: 5 AN: 5754

European-Non Finnish (NFE) AF: 0.00456 AC: 5065 AN: 1109568

Other (OTH) AF: 0.00361 AC: 217 AN: 60138

GnomAD4 genome AF: 0.00336 AC: 512 AN: 152180 Hom.: 0 Cov.: 32 AF XY: 0.00337 AC XY: 251 AN XY: 74406

African (AFR) AF: 0.000915 AC: 38 AN: 41546

American (AMR) AF: 0.00196 AC: 30 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.00144 AC: 5 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.000621 AC: 3 AN: 4828

European-Finnish (FIN) AF: 0.00821 AC: 87 AN: 10594

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.00496 AC: 337 AN: 67964

Other (OTH) AF: 0.00379 AC: 8 AN: 2110

Alfa AF: 0.00456 Hom.: 5

Bravo AF: 0.00291

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	7	not provided (7)
-	-	2	not specified (2)
-	-	1	Connective tissue disorder (1)
-	-	1	Epiphyseal dysplasia, multiple, 6 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Uncertain	-0.030
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.70	D
Eigen	Uncertain	0.59
Eigen_PC	Uncertain	0.63
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.87	D
M_CAP	Uncertain	0.11	D
MetaRNN	Benign	0.015	T
MetaSVM	Uncertain	-0.011	T
MutationAssessor	Benign	0.69	N
PhyloP100		6.0
PrimateAI	Uncertain	0.65	T
PROVEAN	Uncertain	-4.0	D
REVEL	Uncertain	0.54
Sift	Benign	0.046	D
Sift4G	Benign	0.19	T
Varity_R		0.45
gMVP		0.47
Mutation Taster		=96/4	polymorphism

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs77706858;

hg19: chr6-70972993;