rs1048100

Variant names:

• chr20-62840721-C-A
• rs1048100
• NM_001853.4:c.2044C>A

Your query was ambiguous. Multiple possible variants found:

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

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_001853.4(COL9A3):​c.2044C>A​(p.Arg682Arg) 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 (★★). Synonymous variant affecting the same amino acid position (i.e. R682R) has been classified as Likely 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
• Publications: 15 publications found

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 Gene-Disease associations (from GenCC):

• epiphyseal dysplasia, multiple, 3

  Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Ambry Genetics, Illumina, G2P, Labcorp Genetics (formerly Invitae)
• Stickler syndrome

  Inheritance: AR Classification: DEFINITIVE, STRONG, LIMITED Submitted by: Ambry Genetics, Genomics England PanelApp, ClinGen
• Stickler syndrome, type 6

  Inheritance: AR Classification: DEFINITIVE, STRONG, LIMITED Submitted by: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• multiple epiphyseal dysplasia due to collagen 9 anomaly

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• autosomal recessive Stickler syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -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 VariationId is 258420.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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 rank	MANE	Protein	UniProt
COL9A3	NM_001853.4	c.2044C>A	p.Arg682Arg	synonymous_variant	Exon 32 of 32	ENST00000649368.1	NP_001844.3
COL9A3	XM_047439893.1	c.2221C>A	p.Arg741Arg	synonymous_variant	Exon 31 of 31		XP_047295849.1
COL9A3	XM_047439894.1	c.1483C>A	p.Arg495Arg	synonymous_variant	Exon 32 of 32		XP_047295850.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL9A3	ENST00000649368.1	c.2044C>A	p.Arg682Arg	synonymous_variant	Exon 32 of 32		NM_001853.4	ENSP00000496793.1

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

GnomAD2 exomes AF: 0.0975 AC: 17463 AN: 179196 AF XY: 0.0938

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 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

African (AFR) AF: 0.325 AC: 10639 AN: 32744

American (AMR) AF: 0.0627 AC: 2355 AN: 37588

Ashkenazi Jewish (ASJ) AF: 0.0984 AC: 2496 AN: 25366

East Asian (EAS) AF: 0.102 AC: 3840 AN: 37634

South Asian (SAS) AF: 0.0785 AC: 6379 AN: 81242

European-Finnish (FIN) AF: 0.0679 AC: 3439 AN: 50680

Middle Eastern (MID) AF: 0.159 AC: 909 AN: 5716

European-Non Finnish (NFE) AF: 0.0751 AC: 81831 AN: 1089712

Other (OTH) AF: 0.101 AC: 5950 AN: 58816

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

African (AFR) AF: 0.313 AC: 12958 AN: 41448

American (AMR) AF: 0.101 AC: 1546 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.0948 AC: 329 AN: 3472

East Asian (EAS) AF: 0.146 AC: 754 AN: 5164

South Asian (SAS) AF: 0.0883 AC: 425 AN: 4814

European-Finnish (FIN) AF: 0.0660 AC: 699 AN: 10596

Middle Eastern (MID) AF: 0.177 AC: 52 AN: 294

European-Non Finnish (NFE) AF: 0.0816 AC: 5550 AN: 67988

Other (OTH) AF: 0.152 AC: 321 AN: 2112

Alfa AF: 0.0995 Hom.: 4225

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

-

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jun 15, 2017

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not provided Benign:2

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.42
CADD	Benign	0.53
DANN	Benign	0.61
PhyloP100		0.81
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs1048100; hg19: chr20-61472073;