rs741758

chr20-62832149-T-C

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.1288-5T>C variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.355 in 1,603,270 control chromosomes in the GnomAD database, including 105,074 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.37 (11040 hom., cov: 34)
  • Exomes 𝑓: 0.35 (94034 hom.)
• Consequence: COL9A3 NM_001853.4 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.0002446
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 0.0390

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 (BayesDel_noAF=-0.91).
• BP6: Variant 20-62832149-T-C is Benign according to our data. Variant chr20-62832149-T-C is described in ClinVar as [Benign]. Clinvar id is 195872.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-62832149-T-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.463 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL9A3	NM_001853.4	c.1288-5T>C		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000649368.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL9A3	ENST00000649368.1	c.1288-5T>C		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant			NM_001853.4	P1

Frequencies

GnomAD3 genomes AF: 0.372 AC: 56619 AN: 152082 Hom.: 11030 Cov.: 34

Gnomad AFR AF: 0.468

Gnomad AMI AF: 0.242

Gnomad AMR AF: 0.284

Gnomad ASJ AF: 0.307

Gnomad EAS AF: 0.151

Gnomad SAS AF: 0.273

Gnomad FIN AF: 0.382

Gnomad MID AF: 0.376

Gnomad NFE AF: 0.362

Gnomad OTH AF: 0.345

GnomAD3 exomes AF: 0.324 AC: 80834 AN: 249362 Hom.: 14036 AF XY: 0.322 AC XY: 43560 AN XY: 135170

Gnomad AFR exome AF: 0.467

Gnomad AMR exome AF: 0.235

Gnomad ASJ exome AF: 0.286

Gnomad EAS exome AF: 0.162

Gnomad SAS exome AF: 0.274

Gnomad FIN exome AF: 0.387

Gnomad NFE exome AF: 0.363

Gnomad OTH exome AF: 0.329

GnomAD4 exome AF: 0.354 AC: 513087 AN: 1451070 Hom.: 94034 Cov.: 33 AF XY: 0.351 AC XY: 253483 AN XY: 722262

Gnomad4 AFR exome AF: 0.484

Gnomad4 AMR exome AF: 0.242

Gnomad4 ASJ exome AF: 0.297

Gnomad4 EAS exome AF: 0.150

Gnomad4 SAS exome AF: 0.274

Gnomad4 FIN exome AF: 0.381

Gnomad4 NFE exome AF: 0.368

Gnomad4 OTH exome AF: 0.346

GnomAD4 genome AF: 0.372 AC: 56672 AN: 152200 Hom.: 11040 Cov.: 34 AF XY: 0.367 AC XY: 27313 AN XY: 74406

Gnomad4 AFR AF: 0.468

Gnomad4 AMR AF: 0.284

Gnomad4 ASJ AF: 0.307

Gnomad4 EAS AF: 0.151

Gnomad4 SAS AF: 0.273

Gnomad4 FIN AF: 0.382

Gnomad4 NFE AF: 0.362

Gnomad4 OTH AF: 0.345

Alfa AF: 0.358 Hom.: 14000

Bravo AF: 0.370

Asia WGS AF: 0.258 AC: 897 AN: 3478

EpiCase AF: 0.351

EpiControl AF: 0.345

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:7

Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 21, 2015	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 19, 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. -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

Epiphyseal dysplasia, multiple, 3 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 30, 2021

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
Cadd	Benign	2.4
Dann	Benign	0.58

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00024
dbscSNV1_RF	Benign	0.018
SpliceAI score (max)		0.13		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: rs741758; hg19: chr20-61463501; COSMIC: COSV59650443; COSMIC: COSV59650443;