rs117347229

Variant names:

• chr20-62821485-G-A
• rs117347229
• NM_001853.4:c.346-22G>A

Your query was ambiguous. Multiple possible variants found:

• chr20-62821485-G-A
• chr20-62821485-G-C

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.346-22G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0988 in 1,612,528 control chromosomes in the GnomAD database, including 8,618 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). There are indicators that this mutation may affect the branch point..

• Frequency:
  • Genomes: 𝑓 0.086 (678 hom., cov: 33)
  • Exomes 𝑓: 0.10 (7940 hom.)
• Consequence: COL9A3 NM_001853.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 1.09
• Publications: 4 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: This position, referring to a specific DNA site, is a probable branch point but rather VUS (scored 4 / 10). The score ranges from 0 to 10, with values ≤3 considered benign and >5 classified as pathogenic. Computational evidence support a benign effect (BayesDel_noAF=-0.54).
• BP6: Variant 20-62821485-G-A is Benign according to our data. Variant chr20-62821485-G-A is described in ClinVar as Benign. ClinVar VariationId is 258423.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.109 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.346-22G>A		intron	N/A	NP_001844.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL9A3	ENST00000649368.1	MANE Select	c.346-22G>A		intron	N/A	ENSP00000496793.1	Q14050
	COL9A3	ENST00000934236.1		c.346-22G>A		intron	N/A	ENSP00000604295.1
	COL9A3	ENST00000894732.1		c.274-22G>A		intron	N/A	ENSP00000564791.1

Frequencies

GnomAD3 genomes AF: 0.0863 AC: 13125 AN: 152088 Hom.: 680 Cov.: 33

Gnomad AFR AF: 0.0457

Gnomad AMI AF: 0.265

Gnomad AMR AF: 0.0791

Gnomad ASJ AF: 0.119

Gnomad EAS AF: 0.00270

Gnomad SAS AF: 0.107

Gnomad FIN AF: 0.0975

Gnomad MID AF: 0.177

Gnomad NFE AF: 0.111

Gnomad OTH AF: 0.0974

GnomAD2 exomes AF: 0.0910 AC: 22757 AN: 249952 AF XY: 0.0968

Gnomad AFR exome AF: 0.0437

Gnomad AMR exome AF: 0.0589

Gnomad ASJ exome AF: 0.122

Gnomad EAS exome AF: 0.00479

Gnomad FIN exome AF: 0.0939

Gnomad NFE exome AF: 0.108

Gnomad OTH exome AF: 0.105

GnomAD4 exome AF: 0.100 AC: 146200 AN: 1460322 Hom.: 7940 Cov.: 33 AF XY: 0.102 AC XY: 73987 AN XY: 726468

African (AFR) AF: 0.0455 AC: 1525 AN: 33480

American (AMR) AF: 0.0614 AC: 2743 AN: 44702

Ashkenazi Jewish (ASJ) AF: 0.120 AC: 3127 AN: 26124

East Asian (EAS) AF: 0.00307 AC: 122 AN: 39700

South Asian (SAS) AF: 0.126 AC: 10832 AN: 86234

European-Finnish (FIN) AF: 0.0956 AC: 5000 AN: 52290

Middle Eastern (MID) AF: 0.148 AC: 854 AN: 5764

European-Non Finnish (NFE) AF: 0.105 AC: 116191 AN: 1111658

Other (OTH) AF: 0.0962 AC: 5806 AN: 60370

GnomAD4 genome AF: 0.0862 AC: 13113 AN: 152206 Hom.: 678 Cov.: 33 AF XY: 0.0864 AC XY: 6430 AN XY: 74430

African (AFR) AF: 0.0455 AC: 1891 AN: 41544

American (AMR) AF: 0.0790 AC: 1209 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.119 AC: 414 AN: 3470

East Asian (EAS) AF: 0.00271 AC: 14 AN: 5170

South Asian (SAS) AF: 0.107 AC: 519 AN: 4828

European-Finnish (FIN) AF: 0.0975 AC: 1035 AN: 10612

Middle Eastern (MID) AF: 0.170 AC: 50 AN: 294

European-Non Finnish (NFE) AF: 0.111 AC: 7537 AN: 67962

Other (OTH) AF: 0.0959 AC: 202 AN: 2106

Alfa AF: 0.0966 Hom.: 140

Bravo AF: 0.0804

Asia WGS AF: 0.0600 AC: 210 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.54
CADD	Benign	15
DANN	Benign	0.81
PhyloP100		1.1
BranchPoint Hunter		4.0
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs117347229; hg19: chr20-61452837; COSMIC: COSV59652879; COSMIC: COSV59652879;