rs1048100

Positions:

• chr20-62840721-C-A
• chr20-62840721-C-G
• chr20-62840721-C-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_001853.4(COL9A3):​c.2044C>A​(p.Arg682=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0894 in 1,571,590 control chromosomes in the GnomAD database, including 9,005 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.15 (2524 hom., cov: 32)
  • Exomes 𝑓: 0.083 (6481 hom.)
• Consequence: COL9A3 NM_001853.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.811

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=-0.42).
• BP6: Variant 20-62840721-C-A is Benign according to our data. Variant chr20-62840721-C-A is described in ClinVar as [Benign]. Clinvar id is 258420.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-62840721-C-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=0.811 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.308 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COL9A3	NM_001853.4	c.2044C>A	p.Arg682=	synonymous_variant	32/32	ENST00000649368.1	NP_001844.3
COL9A3	XM_047439893.1	c.2221C>A	p.Arg741=	synonymous_variant	31/31		XP_047295849.1
COL9A3	XM_047439894.1	c.1483C>A	p.Arg495=	synonymous_variant	32/32		XP_047295850.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COL9A3	ENST00000649368.1	c.2044C>A	p.Arg682=	synonymous_variant	32/32		NM_001853.4	ENSP00000496793	P1
COL9A3	ENST00000467819.5	n.555C>A		non_coding_transcript_exon_variant	4/4	1
COL9A3	ENST00000462700.5	n.799C>A		non_coding_transcript_exon_variant	6/6	3
COL9A3	ENST00000466192.5	n.1771C>A		non_coding_transcript_exon_variant	8/8	2

Frequencies

GnomAD3 genomes AF: 0.149 AC: 22664 AN: 151974 Hom.: 2521 Cov.: 32

Gnomad AFR AF: 0.313

Gnomad AMI AF: 0.0735

Gnomad AMR AF: 0.101

Gnomad ASJ AF: 0.0948

Gnomad EAS AF: 0.147

Gnomad SAS AF: 0.0882

Gnomad FIN AF: 0.0660

Gnomad MID AF: 0.174

Gnomad NFE AF: 0.0816

Gnomad OTH AF: 0.150

GnomAD3 exomes AF: 0.0975 AC: 17463 AN: 179196 Hom.: 1230 AF XY: 0.0938 AC XY: 8951 AN XY: 95426

Gnomad AFR exome AF: 0.315

Gnomad AMR exome AF: 0.0588

Gnomad ASJ exome AF: 0.0981

Gnomad EAS exome AF: 0.156

Gnomad SAS exome AF: 0.0774

Gnomad FIN exome AF: 0.0661

Gnomad NFE exome AF: 0.0825

Gnomad OTH exome AF: 0.0959

GnomAD4 exome AF: 0.0830 AC: 117838 AN: 1419498 Hom.: 6481 Cov.: 32 AF XY: 0.0828 AC XY: 58101 AN XY: 702042

Gnomad4 AFR exome AF: 0.325

Gnomad4 AMR exome AF: 0.0627

Gnomad4 ASJ exome AF: 0.0984

Gnomad4 EAS exome AF: 0.102

Gnomad4 SAS exome AF: 0.0785

Gnomad4 FIN exome AF: 0.0679

Gnomad4 NFE exome AF: 0.0751

Gnomad4 OTH exome AF: 0.101

GnomAD4 genome AF: 0.149 AC: 22701 AN: 152092 Hom.: 2524 Cov.: 32 AF XY: 0.145 AC XY: 10775 AN XY: 74338

Gnomad4 AFR AF: 0.313

Gnomad4 AMR AF: 0.101

Gnomad4 ASJ AF: 0.0948

Gnomad4 EAS AF: 0.146

Gnomad4 SAS AF: 0.0883

Gnomad4 FIN AF: 0.0660

Gnomad4 NFE AF: 0.0816

Gnomad4 OTH AF: 0.152

Alfa AF: 0.0871 Hom.: 1346

Bravo AF: 0.161

Asia WGS AF: 0.135 AC: 469 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

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	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
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	GeneDx	Jun 15, 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. -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.42
CADD	Benign	0.53
DANN	Benign	0.61

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: rs1048100; hg19: chr20-61472073;