rs150148851

Positions:

• chr20-62824471-C-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_001853.4(COL9A3):​c.546C>T​(p.Pro182=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0115 in 1,599,646 control chromosomes in the GnomAD database, including 145 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0071 (7 hom., cov: 33)
  • Exomes 𝑓: 0.012 (138 hom.)
• Consequence: COL9A3 NM_001853.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -5.76

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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.46).
• BP6: Variant 20-62824471-C-T is Benign according to our data. Variant chr20-62824471-C-T is described in ClinVar as [Benign]. Clinvar id is 258428.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-5.76 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00707 (1076/152184) while in subpopulation NFE AF= 0.0121 (820/67924). AF 95% confidence interval is 0.0114. There are 7 homozygotes in gnomad4. There are 464 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 7 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL9A3	NM_001853.4	c.546C>T	p.Pro182=	synonymous_variant	11/32	ENST00000649368.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL9A3	ENST00000649368.1	c.546C>T	p.Pro182=	synonymous_variant	11/32		NM_001853.4	P1

Frequencies

GnomAD3 genomes AF: 0.00708 AC: 1077 AN: 152066 Hom.: 7 Cov.: 33

Gnomad AFR AF: 0.00222

Gnomad AMI AF: 0.0241

Gnomad AMR AF: 0.00733

Gnomad ASJ AF: 0.00231

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00166

Gnomad FIN AF: 0.000659

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0121

Gnomad OTH AF: 0.00335

GnomAD3 exomes AF: 0.00592 AC: 1335 AN: 225496 Hom.: 14 AF XY: 0.00580 AC XY: 709 AN XY: 122224

Gnomad AFR exome AF: 0.00195

Gnomad AMR exome AF: 0.00541

Gnomad ASJ exome AF: 0.00168

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00178

Gnomad FIN exome AF: 0.00112

Gnomad NFE exome AF: 0.00994

Gnomad OTH exome AF: 0.00841

GnomAD4 exome AF: 0.0119 AC: 17271 AN: 1447462 Hom.: 138 Cov.: 32 AF XY: 0.0113 AC XY: 8151 AN XY: 718984

Gnomad4 AFR exome AF: 0.00213

Gnomad4 AMR exome AF: 0.00550

Gnomad4 ASJ exome AF: 0.00166

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00173

Gnomad4 FIN exome AF: 0.00160

Gnomad4 NFE exome AF: 0.0145

Gnomad4 OTH exome AF: 0.0116

GnomAD4 genome AF: 0.00707 AC: 1076 AN: 152184 Hom.: 7 Cov.: 33 AF XY: 0.00624 AC XY: 464 AN XY: 74418

Gnomad4 AFR AF: 0.00222

Gnomad4 AMR AF: 0.00732

Gnomad4 ASJ AF: 0.00231

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00166

Gnomad4 FIN AF: 0.000659

Gnomad4 NFE AF: 0.0121

Gnomad4 OTH AF: 0.00331

Alfa AF: 0.00876 Hom.: 4

Bravo AF: 0.00757

Asia WGS AF: 0.00115 AC: 4 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Mar 20, 2019	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2024	COL9A3: BP4, BP7, BS1, BS2 -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Sep 08, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	- -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 08, 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, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Connective tissue disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Jun 18, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.46
CADD	Benign	2.8
DANN	Benign	0.85
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs150148851; hg19: chr20-61455823;