rs2294995

Positions:

• chr20-62837219-T-C
• chr20-62837219-T-G

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001853.4(COL9A3):​c.1740T>C​(p.Pro580Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.69 in 1,611,778 control chromosomes in the GnomAD database, including 387,113 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.75 (43619 hom., cov: 32)
  • Exomes 𝑓: 0.68 (343494 hom.)
• Consequence: COL9A3 NM_001853.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -0.940

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.75).
• BP6: Variant 20-62837219-T-C is Benign according to our data. Variant chr20-62837219-T-C is described in ClinVar as [Benign]. Clinvar id is 258417.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-62837219-T-C is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-0.94 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.921 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COL9A3	NM_001853.4	c.1740T>C	p.Pro580Pro	synonymous_variant	30/32	ENST00000649368.1	NP_001844.3
COL9A3	XM_047439893.1	c.1917T>C	p.Pro639Pro	synonymous_variant	29/31		XP_047295849.1
COL9A3	XM_047439894.1	c.1179T>C	p.Pro393Pro	synonymous_variant	30/32		XP_047295850.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COL9A3	ENST00000649368.1	c.1740T>C	p.Pro580Pro	synonymous_variant	30/32		NM_001853.4	ENSP00000496793.1

Frequencies

GnomAD3 genomes AF: 0.748 AC: 113705 AN: 151936 Hom.: 43553 Cov.: 32

Gnomad AFR AF: 0.929

Gnomad AMI AF: 0.678

Gnomad AMR AF: 0.699

Gnomad ASJ AF: 0.729

Gnomad EAS AF: 0.593

Gnomad SAS AF: 0.568

Gnomad FIN AF: 0.681

Gnomad MID AF: 0.794

Gnomad NFE AF: 0.687

Gnomad OTH AF: 0.733

GnomAD3 exomes AF: 0.681 AC: 168289 AN: 247034 Hom.: 58133 AF XY: 0.674 AC XY: 90668 AN XY: 134500

Gnomad AFR exome AF: 0.936

Gnomad AMR exome AF: 0.664

Gnomad ASJ exome AF: 0.712

Gnomad EAS exome AF: 0.598

Gnomad SAS exome AF: 0.591

Gnomad FIN exome AF: 0.679

Gnomad NFE exome AF: 0.688

Gnomad OTH exome AF: 0.683

GnomAD4 exome AF: 0.684 AC: 998414 AN: 1459724 Hom.: 343494 Cov.: 66 AF XY: 0.681 AC XY: 494259 AN XY: 726294

Gnomad4 AFR exome AF: 0.939

Gnomad4 AMR exome AF: 0.668

Gnomad4 ASJ exome AF: 0.711

Gnomad4 EAS exome AF: 0.603

Gnomad4 SAS exome AF: 0.593

Gnomad4 FIN exome AF: 0.682

Gnomad4 NFE exome AF: 0.685

Gnomad4 OTH exome AF: 0.695

GnomAD4 genome AF: 0.749 AC: 113837 AN: 152054 Hom.: 43619 Cov.: 32 AF XY: 0.742 AC XY: 55166 AN XY: 74326

Gnomad4 AFR AF: 0.929

Gnomad4 AMR AF: 0.699

Gnomad4 ASJ AF: 0.729

Gnomad4 EAS AF: 0.593

Gnomad4 SAS AF: 0.569

Gnomad4 FIN AF: 0.681

Gnomad4 NFE AF: 0.687

Gnomad4 OTH AF: 0.733

Alfa AF: 0.693 Hom.: 17491

Bravo AF: 0.762

Asia WGS AF: 0.651 AC: 2266 AN: 3478

EpiCase AF: 0.694

EpiControl AF: 0.695

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

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, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
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	-	- -

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
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	- -

Epiphyseal dysplasia, multiple, 3 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 30, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.75
CADD	Benign	0.79
DANN	Benign	0.54
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.7

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs2294995; hg19: chr20-61468571; COSMIC: COSV58983572; COSMIC: COSV58983572;