rs139401633

Positions:

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 1P and 7B. PP3BP4_ModerateBS1_SupportingBS2

The NM_001853.4(COL9A3):c.388G>A(p.Gly130Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00108 in 1,610,366 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.00090 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0011 ( 3 hom. )

Consequence

COL9A3
NM_001853.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts P:1U:8B:1

Conservation

PhyloP100: 2.92

Variant links:

Genes affected

COL9A3 (HGNC:2219): (collagen type IX alpha 3 chain) This gene encodes one of the three alpha chains of type IX collagen, the major collagen component of hyaline cartilage. Type IX collagen, a heterotrimeric molecule, is usually found in tissues containing type II collagen, a fibrillar collagen. Mutations in this gene are associated with multiple epiphyseal dysplasia type 3. [provided by RefSeq, Jan 2010]

COL9A3 links:

COL9A3 (HGNC:):

COL9A3 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

PP3

Multiple lines of computational evidence support a deleterious effect 8: BayesDel_addAF, BayesDel_noAF, Cadd, Eigen, M_CAP, MutationAssessor, PROVEAN, REVEL [when max_spliceai, FATHMM_MKL, MetaRNN, MutationTaster, phyloP100way_vertebrate was below the threshold]

BP4

Computational evidence support a benign effect (MetaRNN=0.22364005).

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0009 (137/152278) while in subpopulation NFE AF= 0.00147 (100/67990). AF 95% confidence interval is 0.00124. There are 0 homozygotes in gnomad4. There are 61 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

BS2

High Homozygotes in GnomAdExome4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COL9A3	NM_001853.4 linkuse as main transcript	c.388G>A	p.Gly130Ser	missense_variant	8/32	ENST00000649368.1	NP_001844.3	Q14050

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
COL9A3	ENST00000649368.1 linkuse as main transcript	c.388G>A	p.Gly130Ser	missense_variant	8/32		NM_001853.4	ENSP00000496793.1	Q14050
COL9A3	ENST00000452372.2 linkuse as main transcript	c.277G>A	p.Gly93Ser	missense_variant	7/12	5		ENSP00000394280.1	Q4VXW1
COL9A3	ENST00000477612.5 linkuse as main transcript	n.384G>A		non_coding_transcript_exon_variant	8/12	3
COL9A3	ENST00000489045.5 linkuse as main transcript	n.434G>A		non_coding_transcript_exon_variant	7/14	5

Frequencies

GnomAD3 genomes

AF:

0.000907

AC:

138

AN:

152160

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000386

Gnomad AMI

AF:

0.00768

Gnomad AMR

AF:

0.000393

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000753

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00147

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.000829

AC:

202

AN:

243632

Hom.:

AF XY:

0.000805

AC XY:

107

AN XY:

132992

show subpopulations

Gnomad AFR exome

AF:

0.000532

Gnomad AMR exome

AF:

0.000175

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00110

Gnomad NFE exome

AF:

0.00146

Gnomad OTH exome

AF:

0.000846

GnomAD4 exome

AF:

0.00110

AC:

1598

AN:

1458088

Hom.:

Cov.:

AF XY:

0.00105

AC XY:

763

AN XY:

725242

show subpopulations

Gnomad4 AFR exome

AF:

0.000269

Gnomad4 AMR exome

AF:

0.000179

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00108

Gnomad4 NFE exome

AF:

0.00133

Gnomad4 OTH exome

AF:

0.000831

GnomAD4 genome

AF:

0.000900

AC:

137

AN:

152278

Hom.:

Cov.:

AF XY:

0.000819

AC XY:

AN XY:

74462

show subpopulations

Gnomad4 AFR

AF:

0.000385

Gnomad4 AMR

AF:

0.000327

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000753

Gnomad4 NFE

AF:

0.00147

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.000763

Hom.:

Bravo

AF:

0.000831

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.00156

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.00140

AC:

ExAC

AF:

0.000927

AC:

112

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1Uncertain:8Benign:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:5

Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Dec 06, 2016	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Feb 12, 2024	Reported in association with age-related macular degeneration and unspecified retinal and optical nerve disorders (PMID: 24036952); Reported to segregate with autosomal dominant disease in a family with bilateral vitreoretinal lattice degeneration (PMID: 33633367); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 32483926, 35241111, 36621380, 24036952, 33633367) -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 130 of the COL9A3 protein (p.Gly130Ser). This variant is present in population databases (rs139401633, gnomAD 0.1%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with autosomal dominant vitreoretinal degeneration and/or blindness (PMID: 32483926, 33633367). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 392918). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt COL9A3 protein function with a positive predictive value of 95%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2022	COL9A3: PP3 -
Uncertain significance, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Retinal detachment;C0154856:Lattice retinal degeneration

Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

Eye Genetics Research Group, Children's Medical Research Institute

Jul 22, 2020

- -

Epiphyseal dysplasia, multiple, 3

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Mar 31, 2022

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as VUS-3C Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with Stickler syndrome and epiphyseal dysplasia, with or without myopathy (MIM#600969). (I) 0108 - This gene is associated with both recessive and dominant disease. Autosomal recessive inheritance is associated with Stickler syndrome (PMIDs: 24273071, 31090205), while autosomal dominant inheritance is associated with multiple epiphyseal dysplasia, with or without myopathy, and more recently with isolated deafness and retinal phenotypes that overlap with Stickler syndrome (PMID: 33633367). (I) 0115 - Variants in this gene are known to have variable expressivity. Intra- and inter-familial phenotypic variability has been observed in individuals with multiple epiphyseal dysplasia (PMID: 20301302). (I) 0200 - Variant is predicted to result in a missense amino acid change from glycine to serine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD v2 <0.01 for a recessive condition (228 heterozygotes, 0 homozygotes). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0601 - Variant is located at a glycine position within a G-X-Y triple helical repeat (DECIPHER, PMID: 33633367). (SP) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0808 - Previous reports of pathogenicity for this variant are conflicting. This variant has been reported as a VUS five times by clinical laboratories in ClinVar, and once as likely pathogenic in a family with vitreoretinal degeneration and reitinal detachment (PMID: 33633367). (I) 1007 - No published functional evidence has been identified for this variant. (I) 1205 - This variant has been shown to be maternally inherited (by trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

Intervertebral disc disorder;C1832998:Epiphyseal dysplasia, multiple, 3

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Dec 28, 2021

- -

Connective tissue disorder

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Jan 01, 2020

- -

COL9A3-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 02, 2021

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.35

BayesDel_addAF

Pathogenic

0.22

BayesDel_noAF

Pathogenic

0.52

CADD

Pathogenic

DANN

Uncertain

0.99

DEOGEN2

Benign

0.29

T;T;.

Eigen

Pathogenic

0.80

Eigen_PC

Uncertain

0.65

FATHMM_MKL

Uncertain

0.90

LIST_S2

Uncertain

0.96

.;D;D

M_CAP

Pathogenic

0.97

MetaRNN

Benign

0.22

T;T;T

MetaSVM

Pathogenic

0.99

MutationAssessor

Pathogenic

4.6

H;H;.

PrimateAI

Uncertain

0.72

PROVEAN

Pathogenic

-5.1

.;D;D

REVEL

Pathogenic

0.95

Sift

Pathogenic

0.0

.;D;D

Sift4G

Pathogenic

0.0

.;D;D

Polyphen

1.0

D;D;.

Vest4

0.80

MVP

0.96

MPC

0.070

ClinPred

0.32

GERP RS

4.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.82

gMVP

0.94

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