chr21-45421052-A-ACCCCC

Variant names:

• chr21-45421052-A-ACCCCC
• rs71334065
• NM_001379500.1:c.106+15580_106+15584dupCCCCC

Variant summary

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

The NM_001379500.1(COL18A1):​c.106+15580_106+15584dupCCCCC variant causes a intron change involving the alteration of a non-conserved nucleotide. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.00028 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000060 (0 hom.)
  • 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+15580_106+15584dupCCCCC		intron	N/A	NP_001366429.1	P39060-2
	COL18A1-AS1	NR_027498.1		n.1000_1004dupGGGGG		non_coding_transcript_exon	Exon 3 of 3
	COL18A1-AS1	NR_028082.1		n.2084_2088dupGGGGG		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+15580_106+15584dupCCCCC		intron	N/A	ENSP00000498485.1	P39060-2
	COL18A1-AS1	ENST00000397787.5	TSL:1	n.2084_2088dupGGGGG		non_coding_transcript_exon	Exon 3 of 3
	COL18A1-AS1	ENST00000485206.1	TSL:1	n.1000_1004dupGGGGG		non_coding_transcript_exon	Exon 3 of 3

Frequencies

GnomAD3 genomes AF: 0.000279 AC: 42 AN: 150662 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000196

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000264

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000196

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000385

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000355

Gnomad OTH AF: 0.000482

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000600 AC: 3 AN: 50034 Hom.: 0 Cov.: 0 AF XY: 0.0000744 AC XY: 2 AN XY: 26886

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

African (AFR) AF: 0.00 AC: 0 AN: 1414

American (AMR) AF: 0.00 AC: 0 AN: 2876

Ashkenazi Jewish (ASJ) AF: 0.000833 AC: 1 AN: 1200

East Asian (EAS) AF: 0.00 AC: 0 AN: 1828

South Asian (SAS) AF: 0.00 AC: 0 AN: 7918

European-Finnish (FIN) AF: 0.000820 AC: 2 AN: 2438

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 210

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 29456

Other (OTH) AF: 0.00 AC: 0 AN: 2694

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.0000000178044), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.000279 AC: 42 AN: 150768 Hom.: 0 Cov.: 33 AF XY: 0.000245 AC XY: 18 AN XY: 73578

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

African (AFR) AF: 0.000195 AC: 8 AN: 41022

American (AMR) AF: 0.000264 AC: 4 AN: 15174

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3458

East Asian (EAS) AF: 0.000197 AC: 1 AN: 5084

South Asian (SAS) AF: 0.00 AC: 0 AN: 4732

European-Finnish (FIN) AF: 0.000385 AC: 4 AN: 10400

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

European-Non Finnish (NFE) AF: 0.000355 AC: 24 AN: 67602

Other (OTH) AF: 0.000477 AC: 1 AN: 2098

⚠️ 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.

Alfa AF: 0.000162 Hom.: 0

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;