rs751557

Positions:

• chr20-62832170-C-A
• chr20-62832170-C-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001853.4(COL9A3):​c.1304C>A​(p.Ala435Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.2 in 1,605,876 control chromosomes in the GnomAD database, including 35,943 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 (★★). Synonymous variant affecting the same amino acid position (i.e. A435A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.24 (5433 hom., cov: 34)
  • Exomes 𝑓: 0.20 (30510 hom.)
• Consequence: COL9A3 NM_001853.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 0.552

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.012107581).
• BP6: Variant 20-62832170-C-A is Benign according to our data. Variant chr20-62832170-C-A is described in ClinVar as [Benign]. Clinvar id is 195873.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-62832170-C-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.402 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL9A3	NM_001853.4	c.1304C>A	p.Ala435Glu	missense_variant	25/32	ENST00000649368.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL9A3	ENST00000649368.1	c.1304C>A	p.Ala435Glu	missense_variant	25/32		NM_001853.4	P1

Frequencies

GnomAD3 genomes AF: 0.245 AC: 37221 AN: 152156 Hom.: 5424 Cov.: 34

Gnomad AFR AF: 0.407

Gnomad AMI AF: 0.0943

Gnomad AMR AF: 0.158

Gnomad ASJ AF: 0.158

Gnomad EAS AF: 0.0592

Gnomad SAS AF: 0.107

Gnomad FIN AF: 0.205

Gnomad MID AF: 0.228

Gnomad NFE AF: 0.203

Gnomad OTH AF: 0.225

GnomAD3 exomes AF: 0.175 AC: 43549 AN: 249060 Hom.: 4746 AF XY: 0.172 AC XY: 23167 AN XY: 134996

Gnomad AFR exome AF: 0.411

Gnomad AMR exome AF: 0.0981

Gnomad ASJ exome AF: 0.147

Gnomad EAS exome AF: 0.0564

Gnomad SAS exome AF: 0.103

Gnomad FIN exome AF: 0.207

Gnomad NFE exome AF: 0.200

Gnomad OTH exome AF: 0.182

GnomAD4 exome AF: 0.195 AC: 283521 AN: 1453602 Hom.: 30510 Cov.: 33 AF XY: 0.192 AC XY: 138993 AN XY: 723428

Gnomad4 AFR exome AF: 0.423

Gnomad4 AMR exome AF: 0.105

Gnomad4 ASJ exome AF: 0.154

Gnomad4 EAS exome AF: 0.0491

Gnomad4 SAS exome AF: 0.104

Gnomad4 FIN exome AF: 0.202

Gnomad4 NFE exome AF: 0.205

Gnomad4 OTH exome AF: 0.189

GnomAD4 genome AF: 0.245 AC: 37268 AN: 152274 Hom.: 5433 Cov.: 34 AF XY: 0.238 AC XY: 17703 AN XY: 74476

Gnomad4 AFR AF: 0.407

Gnomad4 AMR AF: 0.158

Gnomad4 ASJ AF: 0.158

Gnomad4 EAS AF: 0.0591

Gnomad4 SAS AF: 0.107

Gnomad4 FIN AF: 0.205

Gnomad4 NFE AF: 0.203

Gnomad4 OTH AF: 0.222

Alfa AF: 0.204 Hom.: 4782

Bravo AF: 0.250

TwinsUK AF: 0.221 AC: 820

ALSPAC AF: 0.208 AC: 800

ESP6500AA AF: 0.397 AC: 1747

ESP6500EA AF: 0.206 AC: 1774

ExAC AF: 0.182 AC: 22049

Asia WGS AF: 0.100 AC: 350 AN: 3478

EpiCase AF: 0.193

EpiControl AF: 0.200

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:6

Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
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	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 21, 2015	- -

Epiphyseal dysplasia, multiple, 3 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:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 05, 2018	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. -

Connective tissue disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Jul 18, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.49	T
BayesDel_noAF	Benign	-0.33
CADD	Benign	18
DANN	Benign	0.94
DEOGEN2	Benign	0.00099	T;T
Eigen	Benign	-0.78
Eigen_PC	Benign	-0.66
FATHMM_MKL	Benign	0.24	N
MetaRNN	Benign	0.012	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.64	N;N
MutationTaster	Benign	1.0	P
PrimateAI	Benign	0.36	T
Polyphen		0.081	B;B
Vest4		0.11
MPC		0.40
ClinPred		0.013	T
GERP RS		4.2
Varity_R		0.091
gMVP		0.62

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs751557; hg19: chr20-61463522; COSMIC: COSV59653980; COSMIC: COSV59653980;