chr20-62817090-CGCTCCT-C

Variant names:

• chr20-62817090-CGCTCCT-C
• rs1036479876
• NM_001853.4:c.43_48delCTGCTC

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM2 PM4 BS1_Supporting

The NM_001853.4(COL9A3):​c.43_48delCTGCTC​(p.Leu15_Leu16del) variant causes a conservative inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000563 in 1,242,384 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000056 (0 hom.)
• Consequence: COL9A3 NM_001853.4 conservative_inframe_deletion
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.123

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in NM_001853.4.
• BS1: Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.0000563 (70/1242384) while in subpopulation MID AF= 0.00115 (4/3474). AF 95% confidence interval is 0.000393. There are 0 homozygotes in gnomad4_exome. There are 43 alleles in male gnomad4_exome subpopulation. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL9A3	NM_001853.4	c.43_48delCTGCTC	p.Leu15_Leu16del	conservative_inframe_deletion	Exon 1 of 32	ENST00000649368.1	NP_001844.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL9A3	ENST00000649368.1	c.43_48delCTGCTC	p.Leu15_Leu16del	conservative_inframe_deletion	Exon 1 of 32		NM_001853.4	ENSP00000496793.1
COL9A3	ENST00000477612.5	n.75-460_75-455delCTGCTC		intron_variant	Intron 1 of 11	3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.0000123 AC: 1 AN: 81068 Hom.: 0 AF XY: 0.0000213 AC XY: 1 AN XY: 46948

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000670

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000563 AC: 70 AN: 1242384 Hom.: 0 AF XY: 0.0000702 AC XY: 43 AN XY: 612634

Gnomad4 AFR exome AF: 0.0000400

Gnomad4 AMR exome AF: 0.000289

Gnomad4 ASJ exome AF: 0.0000988

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000183

Gnomad4 FIN exome AF: 0.000134

Gnomad4 NFE exome AF: 0.0000340

Gnomad4 OTH exome AF: 0.000121

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Nov 30, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant, c.43_48del, results in the deletion of 2 amino acid(s) of the COL9A3 protein (p.Leu15_Leu16del), but otherwise preserves the integrity of the reading frame. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has not been reported in the literature in individuals affected with COL9A3-related conditions. Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs1036479876; hg19: chr20-61448442;