rs45476191

Variant names:

• chr20-62824439-C-T
• rs45476191
• NM_001853.4:c.520-6C>T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001853.4(COL9A3):​c.520-6C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0135 in 1,599,674 control chromosomes in the GnomAD database, including 212 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 Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0090 (12 hom., cov: 33)
  • Exomes 𝑓: 0.014 (200 hom.)
• Consequence: COL9A3 NM_001853.4 splice_region, intron
• Scores: Splicing: ADA: 0.0003695
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -0.647

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=-0.62).
• BP6: Variant 20-62824439-C-T is Benign according to our data. Variant chr20-62824439-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 258426.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-62824439-C-T is described in Lovd as [Likely_benign]. Variant chr20-62824439-C-T is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00905 (1378/152272) while in subpopulation SAS AF= 0.0263 (127/4828). AF 95% confidence interval is 0.0226. There are 12 homozygotes in gnomad4. There are 620 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 12 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL9A3	NM_001853.4	c.520-6C>T		splice_region_variant, intron_variant	Intron 10 of 31	ENST00000649368.1	NP_001844.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL9A3	ENST00000649368.1	c.520-6C>T		splice_region_variant, intron_variant	Intron 10 of 31		NM_001853.4	ENSP00000496793.1

Frequencies

GnomAD3 genomes AF: 0.00906 AC: 1379 AN: 152154 Hom.: 12 Cov.: 33

Gnomad AFR AF: 0.00249

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.00301

Gnomad ASJ AF: 0.00432

Gnomad EAS AF: 0.0226

Gnomad SAS AF: 0.0265

Gnomad FIN AF: 0.00226

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.0137

Gnomad OTH AF: 0.00478

GnomAD3 exomes AF: 0.0111 AC: 2512 AN: 225928 Hom.: 25 AF XY: 0.0123 AC XY: 1512 AN XY: 122546

Gnomad AFR exome AF: 0.00115

Gnomad AMR exome AF: 0.00279

Gnomad ASJ exome AF: 0.00188

Gnomad EAS exome AF: 0.0206

Gnomad SAS exome AF: 0.0252

Gnomad FIN exome AF: 0.00191

Gnomad NFE exome AF: 0.0125

Gnomad OTH exome AF: 0.00588

GnomAD4 exome AF: 0.0139 AC: 20138 AN: 1447402 Hom.: 200 Cov.: 32 AF XY: 0.0143 AC XY: 10271 AN XY: 718848

Gnomad4 AFR exome AF: 0.00180

Gnomad4 AMR exome AF: 0.00283

Gnomad4 ASJ exome AF: 0.00286

Gnomad4 EAS exome AF: 0.0188

Gnomad4 SAS exome AF: 0.0253

Gnomad4 FIN exome AF: 0.00301

Gnomad4 NFE exome AF: 0.0146

Gnomad4 OTH exome AF: 0.0110

GnomAD4 genome AF: 0.00905 AC: 1378 AN: 152272 Hom.: 12 Cov.: 33 AF XY: 0.00833 AC XY: 620 AN XY: 74462

Gnomad4 AFR AF: 0.00248

Gnomad4 AMR AF: 0.00301

Gnomad4 ASJ AF: 0.00432

Gnomad4 EAS AF: 0.0228

Gnomad4 SAS AF: 0.0263

Gnomad4 FIN AF: 0.00226

Gnomad4 NFE AF: 0.0137

Gnomad4 OTH AF: 0.00473

Alfa AF: 0.0105 Hom.: 10

Bravo AF: 0.00815

Asia WGS AF: 0.0250 AC: 88 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 02, 2025	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 30, 2020	- -

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Aug 06, 2020	- -
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	-	- -

Intervertebral disc disorder;C1832998:Epiphyseal dysplasia, multiple, 3 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Aug 12, 2021

- -

Connective tissue disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Mar 11, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.62
CADD	Benign	11
DANN	Benign	0.93
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00037
dbscSNV1_RF	Benign	0.022
SpliceAI score (max)		0.19		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: rs45476191; hg19: chr20-61455791;