rs377557569

Variant names:

• chr20-62819308-C-CCCT
• rs377557569
• NM_001853.4:c.255+18_255+20dupTCC

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BS1 BS2

The NM_001853.4(COL9A3):​c.255+18_255+20dupTCC variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00176 in 1,599,436 control chromosomes in the GnomAD database, including 56 homozygotes. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0094 (27 hom., cov: 33)
  • Exomes 𝑓: 0.00096 (29 hom.)
• Consequence: COL9A3 NM_001853.4 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.0780
• Publications: 0 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 -16 ACMG points.

• BP6: Variant 20-62819308-C-CCCT is Benign according to our data. Variant chr20-62819308-C-CCCT is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 258421.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00939 (1430/152304) while in subpopulation AFR AF = 0.033 (1374/41574). AF 95% confidence interval is 0.0316. There are 27 homozygotes in GnomAd4. There are 681 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 27 AR,AD gene

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.255+18_255+20dupTCC		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.255+15_255+16insCCT		intron	N/A	ENSP00000496793.1	Q14050
	COL9A3	ENST00000934236.1		c.255+15_255+16insCCT		intron	N/A	ENSP00000604295.1
	COL9A3	ENST00000894732.1		c.184-621_184-620insCCT		intron	N/A	ENSP00000564791.1

Frequencies

GnomAD3 genomes AF: 0.00937 AC: 1426 AN: 152186 Hom.: 27 Cov.: 33

Gnomad AFR AF: 0.0331

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00249

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00669

GnomAD2 exomes AF: 0.00224 AC: 506 AN: 225648 AF XY: 0.00167

Gnomad AFR exome AF: 0.0328

Gnomad AMR exome AF: 0.00117

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000608

Gnomad OTH exome AF: 0.00109

GnomAD4 exome AF: 0.000960 AC: 1389 AN: 1447132 Hom.: 29 Cov.: 32 AF XY: 0.000841 AC XY: 605 AN XY: 719072

African (AFR) AF: 0.0345 AC: 1150 AN: 33378

American (AMR) AF: 0.00141 AC: 61 AN: 43302

Ashkenazi Jewish (ASJ) AF: 0.0000388 AC: 1 AN: 25752

East Asian (EAS) AF: 0.00 AC: 0 AN: 39294

South Asian (SAS) AF: 0.0000707 AC: 6 AN: 84874

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50694

Middle Eastern (MID) AF: 0.00106 AC: 5 AN: 4728

European-Non Finnish (NFE) AF: 0.0000389 AC: 43 AN: 1105480

Other (OTH) AF: 0.00206 AC: 123 AN: 59630

GnomAD4 genome AF: 0.00939 AC: 1430 AN: 152304 Hom.: 27 Cov.: 33 AF XY: 0.00914 AC XY: 681 AN XY: 74488

African (AFR) AF: 0.0330 AC: 1374 AN: 41574

American (AMR) AF: 0.00248 AC: 38 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10628

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000588 AC: 4 AN: 67988

Other (OTH) AF: 0.00662 AC: 14 AN: 2116

Alfa AF: 0.00534 Hom.: 3

Bravo AF: 0.0109

Asia WGS AF: 0.00144 AC: 5 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.078
Mutation Taster		=100/0	polymorphism

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs377557569; hg19: chr20-61450660;