rs77706858

Positions:

• chr6-70263290-T-C

Variant summary

Our verdict is Benign. Variant got -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:10
• Conservation: PhyloP100: 6.01

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]

ACMG classification

Verdict is Benign. Variant got -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 [Likely_benign]. Clinvar id is 194938.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-70263290-T-C is described in Lovd as [Likely_benign].
• 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 male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 13 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL9A1	NM_001851.6	c.1349A>G	p.Glu450Gly	missense_variant	19/38	ENST00000357250.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL9A1	ENST00000357250.11	c.1349A>G	p.Glu450Gly	missense_variant	19/38	1	NM_001851.6	P1

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

GnomAD3 exomes AF: 0.00364 AC: 907 AN: 249288 Hom.: 2 AF XY: 0.00363 AC XY: 489 AN XY: 134842

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 SAS exome AF: 0.000561

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

Gnomad4 AFR exome AF: 0.000750

Gnomad4 AMR exome AF: 0.00134

Gnomad4 ASJ exome AF: 0.00215

Gnomad4 EAS exome AF: 0.0000253

Gnomad4 SAS exome AF: 0.000624

Gnomad4 FIN exome AF: 0.00892

Gnomad4 NFE exome AF: 0.00456

Gnomad4 OTH exome AF: 0.00361

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

Gnomad4 AFR AF: 0.000915

Gnomad4 AMR AF: 0.00196

Gnomad4 ASJ AF: 0.00144

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000621

Gnomad4 FIN AF: 0.00821

Gnomad4 NFE AF: 0.00496

Gnomad4 OTH AF: 0.00379

Alfa AF: 0.00436 Hom.: 1

Bravo AF: 0.00291

TwinsUK AF: 0.00243 AC: 9

ALSPAC AF: 0.00389 AC: 15

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00419 AC: 36

ExAC AF: 0.00442 AC: 536

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:6

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2023	COL9A1: BS2 -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 18, 2020	This variant is associated with the following publications: (PMID: 26770814, 24828792, 27353947) -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jun 07, 2019	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Nov 15, 2014	- -
Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Epiphyseal dysplasia, multiple, 6 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Mendelics

May 28, 2019

- -

Connective tissue disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Mar 01, 2020

- -

Computational scores

Source: dbNSFP v4.3

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;D
M_CAP	Uncertain	0.11	D
MetaRNN	Benign	0.015	T;T
MetaSVM	Uncertain	-0.011	T
MutationAssessor	Benign	0.69	N;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.65	T
PROVEAN	Uncertain	-4.0	D;D
REVEL	Uncertain	0.54
Sift	Benign	0.046	D;D
Sift4G	Benign	0.19	T;T
Polyphen		1.0	D;D
Vest4		0.65
MVP		0.92
MPC		0.45
ClinPred		0.017	T
GERP RS		5.5
Varity_R		0.45
gMVP		0.47

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

Publications

LitVar

Other links and lift over

dbSNP: rs77706858; hg19: chr6-70972993;