rs1135056

Positions:

chr6-70252130-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The ENST00000357250.11(COL9A1):c.1862A>G(p.Gln621Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.397 in 1,613,484 control chromosomes in the GnomAD database, including 128,924 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q621W) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.38 ( 10978 hom., cov: 32)

Exomes 𝑓: 0.40 ( 117946 hom. )

Consequence

COL9A1
ENST00000357250.11 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 1.73

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.019637465).

BP6

Variant 6-70252130-T-C is Benign according to our data. Variant chr6-70252130-T-C is described in ClinVar as [Benign]. Clinvar id is 258353.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-70252130-T-C is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.412 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COL9A1	NM_001851.6 linkuse as main transcript	c.1862A>G	p.Gln621Arg	missense_variant	28/38	ENST00000357250.11	NP_001842.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COL9A1	ENST00000357250.11 linkuse as main transcript	c.1862A>G	p.Gln621Arg	missense_variant	28/38	1	NM_001851.6	ENSP00000349790	P1	P20849-1

Frequencies

GnomAD3 genomes

AF:

0.378

AC:

57506

AN:

151940

Hom.:

10977

Cov.:

show subpopulations

Gnomad AFR

AF:

0.353

Gnomad AMI

AF:

0.360

Gnomad AMR

AF:

0.319

Gnomad ASJ

AF:

0.431

Gnomad EAS

AF:

0.284

Gnomad SAS

AF:

0.292

Gnomad FIN

AF:

0.394

Gnomad MID

AF:

0.421

Gnomad NFE

AF:

0.416

Gnomad OTH

AF:

0.369

GnomAD3 exomes

AF:

0.371

AC:

93235

AN:

251222

Hom.:

17761

AF XY:

0.373

AC XY:

50705

AN XY:

135818

show subpopulations

Gnomad AFR exome

AF:

0.355

Gnomad AMR exome

AF:

0.293

Gnomad ASJ exome

AF:

0.435

Gnomad EAS exome

AF:

0.283

Gnomad SAS exome

AF:

0.305

Gnomad FIN exome

AF:

0.386

Gnomad NFE exome

AF:

0.420

Gnomad OTH exome

AF:

0.391

GnomAD4 exome

AF:

0.399

AC:

583423

AN:

1461426

Hom.:

117946

Cov.:

AF XY:

0.397

AC XY:

288408

AN XY:

727044

show subpopulations

Gnomad4 AFR exome

AF:

0.353

Gnomad4 AMR exome

AF:

0.295

Gnomad4 ASJ exome

AF:

0.430

Gnomad4 EAS exome

AF:

0.271

Gnomad4 SAS exome

AF:

0.308

Gnomad4 FIN exome

AF:

0.394

Gnomad4 NFE exome

AF:

0.416

Gnomad4 OTH exome

AF:

0.394

GnomAD4 genome

AF:

0.378

AC:

57536

AN:

152058

Hom.:

10978

Cov.:

AF XY:

0.375

AC XY:

27860

AN XY:

74340

show subpopulations

Gnomad4 AFR

AF:

0.353

Gnomad4 AMR

AF:

0.319

Gnomad4 ASJ

AF:

0.431

Gnomad4 EAS

AF:

0.283

Gnomad4 SAS

AF:

0.293

Gnomad4 FIN

AF:

0.394

Gnomad4 NFE

AF:

0.416

Gnomad4 OTH

AF:

0.369

Alfa

AF:

0.409

Hom.:

31533

Bravo

AF:

0.375

TwinsUK

AF:

0.403

AC:

1496

ALSPAC

AF:

0.401

AC:

1545

ESP6500AA

AF:

0.348

AC:

1533

ESP6500EA

AF:

0.414

AC:

3559

ExAC

AF:

0.375

AC:

45542

Asia WGS

AF:

0.294

AC:

1022

AN:

3478

EpiCase

AF:

0.413

EpiControl

AF:

0.419

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 30, 2016	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Epiphyseal dysplasia, multiple, 6

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 30, 2021

- -

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.057

BayesDel_addAF

Benign

-0.56

BayesDel_noAF

Benign

-0.44

CADD

Benign

DANN

Benign

0.70

DEOGEN2

Benign

0.072

T;.

Eigen

Benign

-0.87

Eigen_PC

Benign

-0.70

FATHMM_MKL

Benign

0.0026

LIST_S2

Benign

0.075

T;T

MetaRNN

Benign

0.020

T;T

MetaSVM

Benign

-0.68

MutationAssessor

Benign

-0.10

N;.

MutationTaster

Benign

1.0

P;P;P

PrimateAI

Benign

0.39

PROVEAN

Benign

0.61

N;N

REVEL

Benign

0.28

Sift

Benign

1.0

T;T

Sift4G

Benign

0.70

T;T

Polyphen

0.0010

B;B

Vest4

0.019

MPC

0.077

ClinPred

0.0041

GERP RS

4.9

Varity_R

0.043

gMVP

0.066

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over