chr20-62818517-G-A

Position:

• chr20-62818517-G-A

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1_Moderate PM2 PP5_Very_Strong

The NM_001853.4(COL9A3):​c.148-1G>A variant causes a splice acceptor, intron change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: COL9A3 NM_001853.4 splice_acceptor, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 3.88

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 Pathogenic. Variant got 12 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.01703163 fraction of the gene. Cryptic splice site detected, with MaxEntScore 5.8, offset of 1, new splice context is: tgggtgtctttcctcacaAGgag. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in inframe change.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 20-62818517-G-A is Pathogenic according to our data. Variant chr20-62818517-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 17141.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-62818517-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COL9A3	NM_001853.4	c.148-1G>A		splice_acceptor_variant, intron_variant		ENST00000649368.1	NP_001844.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COL9A3	ENST00000649368.1	c.148-1G>A		splice_acceptor_variant, intron_variant			NM_001853.4	ENSP00000496793.1
COL9A3	ENST00000452372.2	c.37-1G>A		splice_acceptor_variant, intron_variant		5		ENSP00000394280.1
COL9A3	ENST00000477612.5	n.144-1G>A		splice_acceptor_variant, intron_variant		3
COL9A3	ENST00000489045.5	n.194-1G>A		splice_acceptor_variant, intron_variant		5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Nov 27, 2023	This sequence change affects an acceptor splice site in intron 2 of the COL9A3 gene. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), however it is unknown whether splice variants in this region will result in a loss of function. This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individuals with autosomal dominant epiphyseal dysplasia (PMID: 10655510, 10678658). It has also been observed to segregate with disease in related individuals. This variant is also known as G-1IVS2>A, (IVS2,G-A,-1). ClinVar contains an entry for this variant (Variation ID: 17141). Studies have shown that disruption of this splice site results in skipping of exon 3, but is expected to preserve the integrity of the reading-frame (PMID: 10655510, 10678658). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Sep 01, 2016	- -

Epiphyseal dysplasia, multiple, 3 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Juno Genomics, Hangzhou Juno Genomics, Inc

-

PM2_Supporting+PVS1_Strong+PS4_Supporting+PP4+PP1_Strong -

Epiphyseal dysplasia, multiple, 3, with myopathy Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Feb 01, 2000

- -

COL9A3-related disorder Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

May 06, 2024

The COL9A3 c.148-1G>A variant is predicted to disrupt the AG splice acceptor site and interfere with normal splicing. This variant was reported to segregate with disease in two families with multiple epiphyseal dysplasia (Lohiniva et al. 2000. PubMed ID: 10678658; Bönnemann et al. 2000. PubMed ID: 10655510). This variant has not been reported in a large population database, indicating this variant is rare. Variants that disrupt the consensus splice acceptor site in COL9A3 are expected to be pathogenic. This variant is interpreted as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Uncertain	-0.060
CADD	Pathogenic	33
DANN	Uncertain	0.99
Eigen	Pathogenic	0.85
Eigen_PC	Uncertain	0.63
FATHMM_MKL	Benign	0.68	D
GERP RS		4.7
RBP_binding_hub_radar		0.67
RBP_regulation_power_radar		2.5

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.84
SpliceAI score (max)		0.97		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.49		Position offset: 2
DS_AL_spliceai		0.97		Position offset: 1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs606231367; hg19: chr20-61449869;