rs45628843

Positions:

• chr20-62827963-C-T

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.887C>T​(p.Pro296Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0506 in 1,612,860 control chromosomes in the GnomAD database, including 2,435 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 (★★).

• Frequency:
  • Genomes: 𝑓 0.040 (197 hom., cov: 33)
  • Exomes 𝑓: 0.052 (2238 hom.)
• Consequence: COL9A3 NM_001853.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.220

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=0.0029235482).
• BP6: Variant 20-62827963-C-T is Benign according to our data. Variant chr20-62827963-C-T is described in ClinVar as [Benign]. Clinvar id is 258436.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-62827963-C-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0596 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COL9A3	NM_001853.4	c.887C>T	p.Pro296Leu	missense_variant	17/32	ENST00000649368.1	NP_001844.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COL9A3	ENST00000649368.1	c.887C>T	p.Pro296Leu	missense_variant	17/32		NM_001853.4	ENSP00000496793	P1
COL9A3	ENST00000463487.2	n.595C>T		non_coding_transcript_exon_variant	9/11	5

Frequencies

GnomAD3 genomes AF: 0.0399 AC: 6075 AN: 152152 Hom.: 197 Cov.: 33

Gnomad AFR AF: 0.0119

Gnomad AMI AF: 0.0910

Gnomad AMR AF: 0.0445

Gnomad ASJ AF: 0.0380

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00455

Gnomad FIN AF: 0.0364

Gnomad MID AF: 0.0601

Gnomad NFE AF: 0.0612

Gnomad OTH AF: 0.0464

GnomAD3 exomes AF: 0.0387 AC: 9686 AN: 250168 Hom.: 247 AF XY: 0.0388 AC XY: 5260 AN XY: 135624

Gnomad AFR exome AF: 0.00993

Gnomad AMR exome AF: 0.0352

Gnomad ASJ exome AF: 0.0392

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00686

Gnomad FIN exome AF: 0.0373

Gnomad NFE exome AF: 0.0585

Gnomad OTH exome AF: 0.0501

GnomAD4 exome AF: 0.0517 AC: 75547 AN: 1460590 Hom.: 2238 Cov.: 32 AF XY: 0.0507 AC XY: 36852 AN XY: 726612

Gnomad4 AFR exome AF: 0.00968

Gnomad4 AMR exome AF: 0.0364

Gnomad4 ASJ exome AF: 0.0402

Gnomad4 EAS exome AF: 0.0000756

Gnomad4 SAS exome AF: 0.00720

Gnomad4 FIN exome AF: 0.0363

Gnomad4 NFE exome AF: 0.0603

Gnomad4 OTH exome AF: 0.0454

GnomAD4 genome AF: 0.0399 AC: 6071 AN: 152270 Hom.: 197 Cov.: 33 AF XY: 0.0382 AC XY: 2842 AN XY: 74448

Gnomad4 AFR AF: 0.0119

Gnomad4 AMR AF: 0.0444

Gnomad4 ASJ AF: 0.0380

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00456

Gnomad4 FIN AF: 0.0364

Gnomad4 NFE AF: 0.0612

Gnomad4 OTH AF: 0.0459

Alfa AF: 0.0530 Hom.: 286

Bravo AF: 0.0398

TwinsUK AF: 0.0634 AC: 235

ALSPAC AF: 0.0589 AC: 227

ESP6500AA AF: 0.0136 AC: 60

ESP6500EA AF: 0.0613 AC: 527

ExAC AF: 0.0377 AC: 4569

Asia WGS AF: 0.00693 AC: 24 AN: 3478

EpiCase AF: 0.0559

EpiControl AF: 0.0643

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Aug 10, 2018	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 14, 2017	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

Jun 03, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.061
BayesDel_addAF	Benign	-0.38	T
BayesDel_noAF	Benign	-0.27
CADD	Benign	8.9
DANN	Benign	0.60
DEOGEN2	Benign	0.037	T;T
Eigen	Benign	-0.95
Eigen_PC	Benign	-0.96
FATHMM_MKL	Benign	0.16	N
LIST_S2	Benign	0.66	.;T
MetaRNN	Benign	0.0029	T;T
MetaSVM	Benign	-0.61	T
MutationAssessor	Benign	0.70	N;N
MutationTaster	Benign	1.0	D
PrimateAI	Benign	0.43	T
PROVEAN	Uncertain	-3.6	.;D
REVEL	Benign	0.25
Sift	Benign	0.63	.;T
Sift4G	Uncertain	0.050	.;T
Polyphen		0.027	B;B
Vest4		0.062
MPC		0.079
ClinPred		0.016	T
GERP RS		1.1
RBP_binding_hub_radar		1.0
RBP_regulation_power_radar		2.1
Varity_R		0.11
gMVP		0.56

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: rs45628843; hg19: chr20-61459315;