rs61734651

Variant names:

• chr20-62819980-C-T
• rs61734651
• NM_001853.4:c.307C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001853.4(COL9A3):​c.307C>T​(p.Arg103Trp) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0592 in 1,612,252 control chromosomes in the GnomAD database, including 3,307 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 Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R103Q) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.045 (214 hom., cov: 33)
  • Exomes 𝑓: 0.061 (3093 hom.)
• Consequence: COL9A3 NM_001853.4 missense, splice_region
• Scores: Splicing: ADA: 0.7530
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10 O:1
• Conservation: PhyloP100: 0.939
• Publications: 43 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: Illumina, Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P
• Stickler syndrome

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

  Inheritance: AR Classification: DEFINITIVE, STRONG, LIMITED Submitted by: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics
• 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0063285828).
• BP6: Variant 20-62819980-C-T is Benign according to our data. Variant chr20-62819980-C-T is described in ClinVar as Benign. ClinVar VariationId is 17139.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0634 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001853.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL9A3	NM_001853.4	MANE Select	c.307C>T	p.Arg103Trp	missense splice_region	Exon 5 of 32	NP_001844.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL9A3	ENST00000649368.1	MANE Select	c.307C>T	p.Arg103Trp	missense splice_region	Exon 5 of 32	ENSP00000496793.1	Q14050
	COL9A3	ENST00000934236.1		c.307C>T	p.Arg103Trp	missense splice_region	Exon 5 of 33	ENSP00000604295.1
	COL9A3	ENST00000894732.1		c.235C>T	p.Arg79Trp	missense splice_region	Exon 4 of 31	ENSP00000564791.1

Frequencies

GnomAD3 genomes AF: 0.0450 AC: 6823 AN: 151698 Hom.: 214 Cov.: 33

Gnomad AFR AF: 0.0120

Gnomad AMI AF: 0.0352

Gnomad AMR AF: 0.0370

Gnomad ASJ AF: 0.0164

Gnomad EAS AF: 0.000587

Gnomad SAS AF: 0.0295

Gnomad FIN AF: 0.0957

Gnomad MID AF: 0.0446

Gnomad NFE AF: 0.0650

Gnomad OTH AF: 0.0459

GnomAD2 exomes AF: 0.0474 AC: 11845 AN: 249634 AF XY: 0.0488

Gnomad AFR exome AF: 0.0125

Gnomad AMR exome AF: 0.0214

Gnomad ASJ exome AF: 0.0183

Gnomad EAS exome AF: 0.000163

Gnomad FIN exome AF: 0.0968

Gnomad NFE exome AF: 0.0655

Gnomad OTH exome AF: 0.0553

GnomAD4 exome AF: 0.0607 AC: 88695 AN: 1460438 Hom.: 3093 Cov.: 33 AF XY: 0.0602 AC XY: 43731 AN XY: 726546

African (AFR) AF: 0.00941 AC: 315 AN: 33480

American (AMR) AF: 0.0223 AC: 995 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.0196 AC: 513 AN: 26136

East Asian (EAS) AF: 0.000126 AC: 5 AN: 39698

South Asian (SAS) AF: 0.0326 AC: 2808 AN: 86252

European-Finnish (FIN) AF: 0.0933 AC: 4866 AN: 52140

Middle Eastern (MID) AF: 0.0317 AC: 183 AN: 5764

European-Non Finnish (NFE) AF: 0.0684 AC: 76088 AN: 1111880

Other (OTH) AF: 0.0484 AC: 2922 AN: 60374

GnomAD4 genome AF: 0.0449 AC: 6820 AN: 151814 Hom.: 214 Cov.: 33 AF XY: 0.0449 AC XY: 3333 AN XY: 74184

African (AFR) AF: 0.0119 AC: 494 AN: 41432

American (AMR) AF: 0.0370 AC: 565 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.0164 AC: 57 AN: 3468

East Asian (EAS) AF: 0.000588 AC: 3 AN: 5098

South Asian (SAS) AF: 0.0296 AC: 142 AN: 4802

European-Finnish (FIN) AF: 0.0957 AC: 1011 AN: 10566

Middle Eastern (MID) AF: 0.0342 AC: 10 AN: 292

European-Non Finnish (NFE) AF: 0.0650 AC: 4410 AN: 67870

Other (OTH) AF: 0.0454 AC: 96 AN: 2114

Alfa AF: 0.0549 Hom.: 254

Bravo AF: 0.0391

TwinsUK AF: 0.0690 AC: 256

ALSPAC AF: 0.0651 AC: 251

ESP6500AA AF: 0.0145 AC: 64

ESP6500EA AF: 0.0672 AC: 578

ExAC AF: 0.0475 AC: 5759

Asia WGS AF: 0.00982 AC: 35 AN: 3478

EpiCase AF: 0.0583

EpiControl AF: 0.0598

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	3	not provided (3)
-	-	1	Connective tissue disorder (1)
-	-	1	Stickler syndrome (1)
-	-	-	Intervertebral disc disease, susceptibility to (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Uncertain	0.010
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.58	D
Eigen	Uncertain	0.47
Eigen_PC	Uncertain	0.39
FATHMM_MKL	Benign	0.71	D
LIST_S2	Pathogenic	0.97	D
MetaRNN	Benign	0.0063	T
MetaSVM	Uncertain	0.0011	D
MutationAssessor	Uncertain	2.4	M
PhyloP100		0.94
PrimateAI	Uncertain	0.66	T
PROVEAN	Uncertain	-3.2	D
REVEL	Uncertain	0.50
Sift	Uncertain	0.0040	D
Sift4G	Uncertain	0.0030	D
Polyphen		1.0	D
Vest4		0.17
MPC		0.073
ClinPred		0.014	T
GERP RS		3.6
RBP_binding_hub_radar		0.97
RBP_regulation_power_radar		2.7
Varity_R		0.29
gMVP		0.65
Mutation Taster		=98/2	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.75
dbscSNV1_RF	Benign	0.18
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

Other links and lift over

dbSNP: rs61734651; hg19: chr20-61451332; COSMIC: COSV59651862; COSMIC: COSV59651862;