rs760087

Variant names:

• chr20-62836448-A-G
• rs760087
• ENST00000467819.5:n.30A>G

Variant summary

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

The ENST00000467819.5(COL9A3):​n.30A>G variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.166 in 1,612,998 control chromosomes in the GnomAD database, including 25,205 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.16 (2440 hom., cov: 34)
  • Exomes 𝑓: 0.17 (22765 hom.)
• Consequence: COL9A3 ENST00000467819.5 non_coding_transcript_exon
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -1.34
• Publications: 9 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 20-62836448-A-G is Benign according to our data. Variant chr20-62836448-A-G is described in ClinVar as Benign. ClinVar VariationId is 258413.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.438 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL9A3	NM_001853.4	c.1549-30A>G		intron_variant	Intron 28 of 31	ENST00000649368.1	NP_001844.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL9A3	ENST00000649368.1	c.1549-30A>G		intron_variant	Intron 28 of 31		NM_001853.4	ENSP00000496793.1

Frequencies

GnomAD3 genomes AF: 0.161 AC: 24563 AN: 152114 Hom.: 2438 Cov.: 34

Gnomad AFR AF: 0.0982

Gnomad AMI AF: 0.283

Gnomad AMR AF: 0.254

Gnomad ASJ AF: 0.183

Gnomad EAS AF: 0.454

Gnomad SAS AF: 0.153

Gnomad FIN AF: 0.141

Gnomad MID AF: 0.123

Gnomad NFE AF: 0.158

Gnomad OTH AF: 0.178

GnomAD2 exomes AF: 0.192 AC: 47337 AN: 247158 AF XY: 0.186

Gnomad AFR exome AF: 0.0918

Gnomad AMR exome AF: 0.294

Gnomad ASJ exome AF: 0.178

Gnomad EAS exome AF: 0.459

Gnomad FIN exome AF: 0.140

Gnomad NFE exome AF: 0.156

Gnomad OTH exome AF: 0.187

GnomAD4 exome AF: 0.166 AC: 242652 AN: 1460766 Hom.: 22765 Cov.: 36 AF XY: 0.165 AC XY: 119956 AN XY: 726664

African (AFR) AF: 0.0917 AC: 3071 AN: 33472

American (AMR) AF: 0.289 AC: 12868 AN: 44452

Ashkenazi Jewish (ASJ) AF: 0.184 AC: 4812 AN: 26112

East Asian (EAS) AF: 0.440 AC: 17447 AN: 39656

South Asian (SAS) AF: 0.140 AC: 12064 AN: 86166

European-Finnish (FIN) AF: 0.136 AC: 7238 AN: 53270

Middle Eastern (MID) AF: 0.144 AC: 829 AN: 5768

European-Non Finnish (NFE) AF: 0.156 AC: 173771 AN: 1111536

Other (OTH) AF: 0.175 AC: 10552 AN: 60334

GnomAD4 genome AF: 0.161 AC: 24566 AN: 152232 Hom.: 2440 Cov.: 34 AF XY: 0.164 AC XY: 12181 AN XY: 74438

African (AFR) AF: 0.0980 AC: 4073 AN: 41564

American (AMR) AF: 0.254 AC: 3884 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.183 AC: 633 AN: 3468

East Asian (EAS) AF: 0.453 AC: 2350 AN: 5184

South Asian (SAS) AF: 0.153 AC: 739 AN: 4820

European-Finnish (FIN) AF: 0.141 AC: 1491 AN: 10606

Middle Eastern (MID) AF: 0.119 AC: 35 AN: 294

European-Non Finnish (NFE) AF: 0.158 AC: 10725 AN: 67990

Other (OTH) AF: 0.180 AC: 380 AN: 2114

Alfa AF: 0.164 Hom.: 2995

Bravo AF: 0.170

Asia WGS AF: 0.289 AC: 1005 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jul 15, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:1

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	0.77
DANN	Benign	0.41
PhyloP100		-1.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs760087; hg19: chr20-61467800; COSMIC: COSV58983568; COSMIC: COSV58983568;