21-45421052-AC-ACCCCCCCCCCCCCCC

Variant names:

• chr21-45421052-A-ACCCCCCCCCCCCCC
• rs71334065
• NM_001379500.1:c.106+15584_106+15585insCCCCCCCCCCCCCC

Variant summary

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

The NM_001379500.1(COL18A1):​c.106+15584_106+15585insCCCCCCCCCCCCCC variant causes a intron change involving the alteration of a non-conserved nucleotide. 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.000093 (0 hom., cov: 33)
  • Failed GnomAD Quality Control
• Consequence: COL18A1 NM_001379500.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.451
• Publications: 0 publications found

Genes affected

COL18A1 (HGNC:2195): (collagen type XVIII alpha 1 chain) This gene encodes the alpha chain of type XVIII collagen. This collagen is one of the multiplexins, extracellular matrix proteins that contain multiple triple-helix domains (collagenous domains) interrupted by non-collagenous domains. A long isoform of the protein has an N-terminal domain that is homologous to the extracellular part of frizzled receptors. Proteolytic processing at several endogenous cleavage sites in the C-terminal domain results in production of endostatin, a potent antiangiogenic protein that is able to inhibit angiogenesis and tumor growth. Mutations in this gene are associated with Knobloch syndrome. The main features of this syndrome involve retinal abnormalities, so type XVIII collagen may play an important role in retinal structure and in neural tube closure. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Dec 2014]

COL18A1-AS1 (HGNC:23132): (COL18A1 antisense RNA 1)

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001379500.1. 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
	COL18A1	NM_001379500.1	MANE Select	c.106+15584_106+15585insCCCCCCCCCCCCCC		intron	N/A	NP_001366429.1	P39060-2
	COL18A1-AS1	NR_027498.1		n.1004_1005insGGGGGGGGGGGGGG		non_coding_transcript_exon	Exon 3 of 3
	COL18A1-AS1	NR_028082.1		n.2088_2089insGGGGGGGGGGGGGG		non_coding_transcript_exon	Exon 3 of 3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL18A1	ENST00000651438.1	MANE Select	c.106+15584_106+15585insCCCCCCCCCCCCCC		intron	N/A	ENSP00000498485.1	P39060-2
	COL18A1-AS1	ENST00000397787.5	TSL:1	n.2088_2089insGGGGGGGGGGGGGG		non_coding_transcript_exon	Exon 3 of 3
	COL18A1-AS1	ENST00000485206.1	TSL:1	n.1004_1005insGGGGGGGGGGGGGG		non_coding_transcript_exon	Exon 3 of 3

Frequencies

GnomAD3 genomes AF: 0.0000929 AC: 14 AN: 150664 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000733

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000132

Gnomad ASJ AF: 0.000289

Gnomad EAS AF: 0.000393

Gnomad SAS AF: 0.000423

Gnomad FIN AF: 0.0000961

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000296

Gnomad OTH AF: 0.000482

GnomAD4 exome Cov.: 0

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000929 AC: 14 AN: 150774 Hom.: 0 Cov.: 33 AF XY: 0.000109 AC XY: 8 AN XY: 73564

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0000731 AC: 3 AN: 41028

American (AMR) AF: 0.000132 AC: 2 AN: 15170

Ashkenazi Jewish (ASJ) AF: 0.000289 AC: 1 AN: 3460

East Asian (EAS) AF: 0.000394 AC: 2 AN: 5074

South Asian (SAS) AF: 0.000424 AC: 2 AN: 4718

European-Finnish (FIN) AF: 0.0000961 AC: 1 AN: 10402

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.0000296 AC: 2 AN: 67628

Other (OTH) AF: 0.000477 AC: 1 AN: 2096

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.45

Splicing

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

Other links and lift over

dbSNP: rs71334065; hg19: chr21-46840967;