20-62830443-TGGG-TGGGG

Variant names:

• chr20-62830443-T-TG
• rs397840562
• NM_001853.4:c.1215+36dupG

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_001853.4(COL9A3):​c.1215+36dupG variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.184 in 1,573,964 control chromosomes in the GnomAD database, including 27,501 homozygotes. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.20 (3376 hom., cov: 28)
  • Exomes 𝑓: 0.18 (24125 hom.)
• Consequence: COL9A3 NM_001853.4 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.75
• Publications: 1 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 -16 ACMG points.

• BP6: Variant 20-62830443-T-TG is Benign according to our data. Variant chr20-62830443-T-TG is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 258404.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.277 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL9A3	NM_001853.4	c.1215+36dupG		intron_variant	Intron 23 of 31	ENST00000649368.1	NP_001844.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL9A3	ENST00000649368.1	c.1215+30_1215+31insG		intron_variant	Intron 23 of 31		NM_001853.4	ENSP00000496793.1

Frequencies

GnomAD3 genomes AF: 0.203 AC: 30742 AN: 151546 Hom.: 3367 Cov.: 28

Gnomad AFR AF: 0.282

Gnomad AMI AF: 0.148

Gnomad AMR AF: 0.168

Gnomad ASJ AF: 0.169

Gnomad EAS AF: 0.0915

Gnomad SAS AF: 0.172

Gnomad FIN AF: 0.185

Gnomad MID AF: 0.215

Gnomad NFE AF: 0.179

Gnomad OTH AF: 0.183

GnomAD2 exomes AF: 0.174 AC: 32273 AN: 185700 AF XY: 0.172

Gnomad AFR exome AF: 0.274

Gnomad AMR exome AF: 0.159

Gnomad ASJ exome AF: 0.157

Gnomad EAS exome AF: 0.103

Gnomad FIN exome AF: 0.183

Gnomad NFE exome AF: 0.178

Gnomad OTH exome AF: 0.170

GnomAD4 exome AF: 0.182 AC: 258266 AN: 1422300 Hom.: 24125 Cov.: 35 AF XY: 0.181 AC XY: 127379 AN XY: 704012

African (AFR) AF: 0.297 AC: 9756 AN: 32814

American (AMR) AF: 0.162 AC: 6227 AN: 38534

Ashkenazi Jewish (ASJ) AF: 0.163 AC: 4125 AN: 25322

East Asian (EAS) AF: 0.0994 AC: 3766 AN: 37874

South Asian (SAS) AF: 0.175 AC: 14252 AN: 81580

European-Finnish (FIN) AF: 0.185 AC: 9086 AN: 49214

Middle Eastern (MID) AF: 0.197 AC: 1126 AN: 5720

European-Non Finnish (NFE) AF: 0.182 AC: 198839 AN: 1092374

Other (OTH) AF: 0.188 AC: 11089 AN: 58868

GnomAD4 genome AF: 0.203 AC: 30783 AN: 151664 Hom.: 3376 Cov.: 28 AF XY: 0.201 AC XY: 14918 AN XY: 74120

African (AFR) AF: 0.282 AC: 11633 AN: 41294

American (AMR) AF: 0.168 AC: 2564 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.169 AC: 586 AN: 3466

East Asian (EAS) AF: 0.0916 AC: 471 AN: 5144

South Asian (SAS) AF: 0.172 AC: 828 AN: 4814

European-Finnish (FIN) AF: 0.185 AC: 1959 AN: 10574

Middle Eastern (MID) AF: 0.214 AC: 63 AN: 294

European-Non Finnish (NFE) AF: 0.179 AC: 12154 AN: 67796

Other (OTH) AF: 0.185 AC: 391 AN: 2108

Alfa AF: 0.193 Hom.: 501

Bravo AF: 0.204

Asia WGS AF: 0.170 AC: 593 AN: 3476

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not provided Benign:1

Oct 04, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		-1.7
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
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: rs397840562; hg19: chr20-61461795; COSMIC: COSV107417499; COSMIC: COSV107417499;