rs2294995

Variant names:

• chr20-62837219-T-C
• rs2294995
• NM_001853.4:c.1740T>C

Your query was ambiguous. Multiple possible variants found:

• chr20-62837219-T-C
• chr20-62837219-T-A
• chr20-62837219-T-G

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001853.4(COL9A3):​c.1740T>C​(p.Pro580Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.69 in 1,611,778 control chromosomes in the GnomAD database, including 387,113 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.75 (43619 hom., cov: 32)
  • Exomes 𝑓: 0.68 (343494 hom.)
• Consequence: COL9A3 NM_001853.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -0.940
• Publications: 18 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.75).
• BP6: Variant 20-62837219-T-C is Benign according to our data. Variant chr20-62837219-T-C is described in ClinVar as Benign. ClinVar VariationId is 258417.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.94 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.921 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.1740T>C	p.Pro580Pro	synonymous	Exon 30 of 32	NP_001844.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL9A3	ENST00000649368.1	MANE Select	c.1740T>C	p.Pro580Pro	synonymous	Exon 30 of 32	ENSP00000496793.1	Q14050
	COL9A3	ENST00000467819.5	TSL:1	n.251T>C		non_coding_transcript_exon	Exon 2 of 4
	COL9A3	ENST00000934236.1		c.1791T>C	p.Pro597Pro	synonymous	Exon 31 of 33	ENSP00000604295.1

Frequencies

GnomAD3 genomes AF: 0.748 AC: 113705 AN: 151936 Hom.: 43553 Cov.: 32

Gnomad AFR AF: 0.929

Gnomad AMI AF: 0.678

Gnomad AMR AF: 0.699

Gnomad ASJ AF: 0.729

Gnomad EAS AF: 0.593

Gnomad SAS AF: 0.568

Gnomad FIN AF: 0.681

Gnomad MID AF: 0.794

Gnomad NFE AF: 0.687

Gnomad OTH AF: 0.733

GnomAD2 exomes AF: 0.681 AC: 168289 AN: 247034 AF XY: 0.674

Gnomad AFR exome AF: 0.936

Gnomad AMR exome AF: 0.664

Gnomad ASJ exome AF: 0.712

Gnomad EAS exome AF: 0.598

Gnomad FIN exome AF: 0.679

Gnomad NFE exome AF: 0.688

Gnomad OTH exome AF: 0.683

GnomAD4 exome AF: 0.684 AC: 998414 AN: 1459724 Hom.: 343494 Cov.: 66 AF XY: 0.681 AC XY: 494259 AN XY: 726294

African (AFR) AF: 0.939 AC: 31449 AN: 33476

American (AMR) AF: 0.668 AC: 29847 AN: 44702

Ashkenazi Jewish (ASJ) AF: 0.711 AC: 18552 AN: 26110

East Asian (EAS) AF: 0.603 AC: 23923 AN: 39696

South Asian (SAS) AF: 0.593 AC: 51183 AN: 86244

European-Finnish (FIN) AF: 0.682 AC: 35158 AN: 51570

Middle Eastern (MID) AF: 0.747 AC: 4294 AN: 5746

European-Non Finnish (NFE) AF: 0.685 AC: 762031 AN: 1111822

Other (OTH) AF: 0.695 AC: 41977 AN: 60358

GnomAD4 genome AF: 0.749 AC: 113837 AN: 152054 Hom.: 43619 Cov.: 32 AF XY: 0.742 AC XY: 55166 AN XY: 74326

African (AFR) AF: 0.929 AC: 38568 AN: 41522

American (AMR) AF: 0.699 AC: 10683 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.729 AC: 2528 AN: 3466

East Asian (EAS) AF: 0.593 AC: 3046 AN: 5134

South Asian (SAS) AF: 0.569 AC: 2739 AN: 4810

European-Finnish (FIN) AF: 0.681 AC: 7200 AN: 10576

Middle Eastern (MID) AF: 0.799 AC: 235 AN: 294

European-Non Finnish (NFE) AF: 0.687 AC: 46672 AN: 67942

Other (OTH) AF: 0.733 AC: 1549 AN: 2112

Alfa AF: 0.698 Hom.: 20566

Bravo AF: 0.762

Asia WGS AF: 0.651 AC: 2266 AN: 3478

EpiCase AF: 0.694

EpiControl AF: 0.695

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	Epiphyseal dysplasia, multiple, 3 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.75
CADD	Benign	0.79
DANN	Benign	0.54
PhyloP100		-0.94
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.7
Mutation Taster		=99/1	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: rs2294995; hg19: chr20-61468571; COSMIC: COSV58983572; COSMIC: COSV58983572;