NM_001853.4:c.37_48dupCTGCTCCTGCTC

Variant names:

• chr20-62817090-C-CGCTCCTGCTCCT
• rs1036479876
• NM_001853.4:c.37_48dupCTGCTCCTGCTC

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM4

The NM_001853.4(COL9A3):​c.37_48dupCTGCTCCTGCTC​(p.Leu13_Leu16dup) variant causes a conservative inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000965 in 1,243,348 control chromosomes in the GnomAD database, with no homozygous occurrence. It is difficult to determine the true allele frequency of this variant because it is of type INS_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. G17G) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000097 (0 hom.)
• Consequence: COL9A3 NM_001853.4 conservative_inframe_insertion
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.107
• 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: Uncertain_significance. The variant received 2 ACMG points.

• PM4: Nonframeshift variant in NON repetitive region in NM_001853.4.

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.37_48dupCTGCTCCTGCTC	p.Leu13_Leu16dup	conservative_inframe_insertion	Exon 1 of 32	NP_001844.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL9A3	ENST00000649368.1	MANE Select	c.37_48dupCTGCTCCTGCTC	p.Leu13_Leu16dup	conservative_inframe_insertion	Exon 1 of 32	ENSP00000496793.1	Q14050
	COL9A3	ENST00000934236.1		c.37_48dupCTGCTCCTGCTC	p.Leu13_Leu16dup	conservative_inframe_insertion	Exon 1 of 33	ENSP00000604295.1
	COL9A3	ENST00000894732.1		c.37_48dupCTGCTCCTGCTC	p.Leu13_Leu16dup	conservative_inframe_insertion	Exon 1 of 31	ENSP00000564791.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000965 AC: 12 AN: 1243348 Hom.: 0 Cov.: 30 AF XY: 0.0000147 AC XY: 9 AN XY: 613188

African (AFR) AF: 0.0000400 AC: 1 AN: 25030

American (AMR) AF: 0.00 AC: 0 AN: 24232

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 20268

East Asian (EAS) AF: 0.0000408 AC: 1 AN: 24524

South Asian (SAS) AF: 0.00 AC: 0 AN: 65682

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 29856

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3484

European-Non Finnish (NFE) AF: 0.00000999 AC: 10 AN: 1000802

Other (OTH) AF: 0.00 AC: 0 AN: 49470

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.11

Splicing

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

Other links and lift over

dbSNP: rs1036479876; hg19: chr20-61448442;