6-70234554-T-C

Position:

chr6-70234554-T-C

Variant summary

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

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. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt.

Frequency

Genomes: 𝑓 0.045 ( 278 hom., cov: 32)

Exomes 𝑓: 0.021 ( 815 hom. )

Consequence

COL9A1
NM_001851.6 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 1.81

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:

ENSG00000253809 (HGNC:):

ENSG00000253809 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=0.002387613).

BP6

Variant 6-70234554-T-C is Benign according to our data. Variant chr6-70234554-T-C is described in ClinVar as [Benign]. Clinvar id is 258358.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-70234554-T-C is described in Lovd as [Benign]. Variant chr6-70234554-T-C is described in Lovd as [Likely_benign].

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.102 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COL9A1	NM_001851.6 link	c.2299A>G	p.Met767Val	missense_variant	35/38	ENST00000357250.11	NP_001842.3	P20849-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COL9A1	ENST00000357250.11 link	c.2299A>G	p.Met767Val	missense_variant	35/38	1	NM_001851.6	ENSP00000349790.6		P20849-1

Frequencies

GnomAD3 genomes

AF:

0.0449

AC:

6828

AN:

152160

Hom.:

278

Cov.:

show subpopulations

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

GnomAD3 exomes

AF:

0.0394

AC:

9914

AN:

251372

Hom.:

419

AF XY:

0.0338

AC XY:

4591

AN XY:

135868

show subpopulations

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 SAS exome

AF:

0.0115

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.:

AF XY:

0.0195

AC XY:

14157

AN XY:

727222

show subpopulations

Gnomad4 AFR exome

AF:

0.101

Gnomad4 AMR exome

AF:

0.103

Gnomad4 ASJ exome

AF:

0.0486

Gnomad4 EAS exome

AF:

0.0960

Gnomad4 SAS exome

AF:

0.0118

Gnomad4 FIN exome

AF:

0.00683

Gnomad4 NFE exome

AF:

0.0122

Gnomad4 OTH exome

AF:

0.0311

GnomAD4 genome

AF:

0.0449

AC:

6838

AN:

152278

Hom.:

278

Cov.:

AF XY:

0.0453

AC XY:

3375

AN XY:

74450

show subpopulations

Gnomad4 AFR

AF:

0.0976

Gnomad4 AMR

AF:

0.0606

Gnomad4 ASJ

AF:

0.0542

Gnomad4 EAS

AF:

0.109

Gnomad4 SAS

AF:

0.0174

Gnomad4 FIN

AF:

0.00593

Gnomad4 NFE

AF:

0.0127

Gnomad4 OTH

AF:

0.0384

Alfa

AF:

0.0239

Hom.:

153

Bravo

AF:

0.0533

TwinsUK

AF:

0.0111

AC:

ALSPAC

AF:

0.0132

AC:

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

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
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	Oct 06, 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, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -

not provided

Benign:3

Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Aug 10, 2018	- -
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

0.13

BayesDel_addAF

Benign

-0.36

BayesDel_noAF

Benign

-0.20

CADD

Benign

DANN

Benign

0.93

DEOGEN2

Benign

0.14

T;.

Eigen

Benign

-0.20

Eigen_PC

Benign

-0.051

FATHMM_MKL

Uncertain

0.93

LIST_S2

Uncertain

0.88

D;D

MetaRNN

Benign

0.0024

T;T

MetaSVM

Uncertain

-0.21

MutationAssessor

Benign

1.6

L;.

PrimateAI

Benign

0.47

PROVEAN

Benign

-1.5

N;N

REVEL

Uncertain

0.33

Sift

Benign

0.27

T;T

Sift4G

Benign

0.19

T;T

Polyphen

0.25

B;B

Vest4

0.12

MPC

0.081

ClinPred

0.0031

GERP RS

3.3

Varity_R

0.32

gMVP

0.60

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

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