rs592121

Positions:

Variant summary

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

The ENST00000357250.11(COL9A1):c.1015T>C(p.Ser339Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.396 in 1,608,134 control chromosomes in the GnomAD database, including 130,770 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.46 ( 17851 hom., cov: 32)

Exomes 𝑓: 0.39 ( 112919 hom. )

Consequence

COL9A1
ENST00000357250.11 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: 2.51

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=3.3340893E-6).

BP6

Variant 6-70274733-A-G is Benign according to our data. Variant chr6-70274733-A-G is described in ClinVar as [Benign]. Clinvar id is 258335.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-70274733-A-G is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.67 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.1015T>C	p.Ser339Pro	missense_variant	11/38	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.1015T>C	p.Ser339Pro	missense_variant	11/38	1	NM_001851.6	ENSP00000349790	P1	P20849-1

Frequencies

GnomAD3 genomes

AF:

0.464

AC:

70492

AN:

151840

Hom.:

17804

Cov.:

show subpopulations

Gnomad AFR

AF:

0.677

Gnomad AMI

AF:

0.259

Gnomad AMR

AF:

0.418

Gnomad ASJ

AF:

0.352

Gnomad EAS

AF:

0.339

Gnomad SAS

AF:

0.461

Gnomad FIN

AF:

0.322

Gnomad MID

AF:

0.459

Gnomad NFE

AF:

0.387

Gnomad OTH

AF:

0.438

GnomAD3 exomes

AF:

0.395

AC:

99156

AN:

250848

Hom.:

20761

AF XY:

0.395

AC XY:

53610

AN XY:

135574

show subpopulations

Gnomad AFR exome

AF:

0.687

Gnomad AMR exome

AF:

0.322

Gnomad ASJ exome

AF:

0.346

Gnomad EAS exome

AF:

0.343

Gnomad SAS exome

AF:

0.453

Gnomad FIN exome

AF:

0.321

Gnomad NFE exome

AF:

0.387

Gnomad OTH exome

AF:

0.389

GnomAD4 exome

AF:

0.389

AC:

566143

AN:

1456174

Hom.:

112919

Cov.:

AF XY:

0.390

AC XY:

282842

AN XY:

724768

show subpopulations

Gnomad4 AFR exome

AF:

0.693

Gnomad4 AMR exome

AF:

0.332

Gnomad4 ASJ exome

AF:

0.348

Gnomad4 EAS exome

AF:

0.370

Gnomad4 SAS exome

AF:

0.451

Gnomad4 FIN exome

AF:

0.329

Gnomad4 NFE exome

AF:

0.381

Gnomad4 OTH exome

AF:

0.395

GnomAD4 genome

AF:

0.465

AC:

70592

AN:

151960

Hom.:

17851

Cov.:

AF XY:

0.461

AC XY:

34237

AN XY:

74266

show subpopulations

Gnomad4 AFR

AF:

0.677

Gnomad4 AMR

AF:

0.418

Gnomad4 ASJ

AF:

0.352

Gnomad4 EAS

AF:

0.338

Gnomad4 SAS

AF:

0.462

Gnomad4 FIN

AF:

0.322

Gnomad4 NFE

AF:

0.387

Gnomad4 OTH

AF:

0.442

Alfa

AF:

0.393

Hom.:

28967

Bravo

AF:

0.475

TwinsUK

AF:

0.381

AC:

1413

ALSPAC

AF:

0.372

AC:

1433

ESP6500AA

AF:

0.679

AC:

2993

ESP6500EA

AF:

0.378

AC:

3247

ExAC

AF:

0.406

AC:

49336

Asia WGS

AF:

0.413

AC:

1438

AN:

3478

EpiCase

AF:

0.389

EpiControl

AF:

0.385

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:6

Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 29, 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. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -

Epiphyseal dysplasia, multiple, 6

Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 30, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -

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

0.048

BayesDel_addAF

Benign

-0.53

BayesDel_noAF

Benign

-0.39

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.22

T;.

Eigen

Benign

-0.83

Eigen_PC

Benign

-0.49

FATHMM_MKL

Benign

0.022

LIST_S2

Benign

0.39

T;T

MetaRNN

Benign

0.0000033

T;T

MetaSVM

Benign

-0.90

MutationAssessor

Benign

-1.4

N;.

MutationTaster

Benign

1.0

P;P;P

PrimateAI

Uncertain

0.53

PROVEAN

Benign

2.9

N;N

REVEL

Uncertain

0.38

Sift

Benign

1.0

T;T

Sift4G

Benign

0.94

T;T

Polyphen

0.0010

B;B

Vest4

0.052

MPC

0.087

ClinPred

0.0068

GERP RS

5.0

Varity_R

0.15

gMVP

0.18

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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