rs139401633

chr20-62821775-G-Achr20-62821775-G-C

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 1P and 3B. PP3 BP4_Moderate BS1_Supporting

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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G130V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00090 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0011 (3 hom.)
• Consequence: COL9A3 NM_001853.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:6 B:1
• Conservation: PhyloP100: 2.92

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]

ACMG classification

Verdict is Likely_benign. Variant got -2 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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL9A3	NM_001853.4	c.388G>A	p.Gly130Ser	missense_variant	8/32	ENST00000649368.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL9A3	ENST00000649368.1	c.388G>A	p.Gly130Ser	missense_variant	8/32		NM_001853.4	P1
COL9A3	ENST00000452372.2	c.277G>A	p.Gly93Ser	missense_variant	7/12	5
COL9A3	ENST00000477612.5	n.384G>A		non_coding_transcript_exon_variant	8/12	3
COL9A3	ENST00000489045.5	n.434G>A		non_coding_transcript_exon_variant	7/14	5

Frequencies

GnomAD3 genomes AF: 0.000907 AC: 138 AN: 152160 Hom.: 0 Cov.: 33

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.: 0 AF XY: 0.000805 AC XY: 107 AN XY: 132992

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.: 3 Cov.: 32 AF XY: 0.00105 AC XY: 763 AN XY: 725242

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.: 0 Cov.: 33 AF XY: 0.000819 AC XY: 61 AN XY: 74462

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.: 0

Bravo AF: 0.000831

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.00156 AC: 6

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00140 AC: 12

ExAC AF: 0.000927 AC: 112

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:6 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:4

Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Dec 06, 2016	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jul 03, 2023	Reported in association with age-related macular degeneration and unspecified retinal and optical nerve disorders (Seddon et al., 2013; Dieiro et al., 2020); Reported to segregate with autosomal dominant disease in a family with bilateral vitreoretinal lattice degeneration (Nash et al., 2021); 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, 33633367, 24036952, 36621380) -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	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 -

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

- -

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, criteria provided, single submitter

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	D
BayesDel_noAF	Pathogenic	0.52
Cadd	Pathogenic	26
Dann	Uncertain	0.99
DEOGEN2	Benign	0.29	T;T;.
Eigen	Pathogenic	0.80
Eigen_PC	Uncertain	0.65
FATHMM_MKL	Uncertain	0.90	D
M_CAP	Pathogenic	0.97	D
MetaRNN	Benign	0.22	T;T;T
MetaSVM	Pathogenic	0.99	D
MutationAssessor	Pathogenic	4.6	H;H;.
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.72	T
Polyphen		1.0	D;D;.
Vest4		0.80
MVP		0.96
MPC		0.070
ClinPred		0.32	T
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

Other links and lift over

dbSNP: rs139401633; hg19: chr20-61453127;