rs752078007

Positions:

• chr21-45455594-C-CG

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PVS1_Strong

The NM_130444.3(COL18A1):​c.67dupG​(p.Ala23fs) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000301 in 1,461,604 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.000030 (0 hom.)
• Consequence: COL18A1 NM_130444.3 frameshift
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: -1.92

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 6 pathogenic variants in the truncated region.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COL18A1	NM_001379500.1	c.107-12645dupG		intron_variant		ENST00000651438.1	NP_001366429.1
COL18A1	NM_130444.3	c.67dupG	p.Ala23fs	frameshift_variant	1/41		NP_569711.2
COL18A1	NM_030582.4	c.67dupG	p.Ala23fs	frameshift_variant	1/41		NP_085059.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COL18A1	ENST00000355480.10	c.67dupG	p.Ala23fs	frameshift_variant	1/41	1		ENSP00000347665.5
COL18A1	ENST00000651438.1	c.107-12645dupG		intron_variant			NM_001379500.1	ENSP00000498485.1
COL18A1	ENST00000359759.8	c.67dupG	p.Ala23fs	frameshift_variant	1/41	5		ENSP00000352798.4

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD3 exomes AF: 0.0000161 AC: 4 AN: 249170 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135292

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000290

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: 0.0000266

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000301 AC: 44 AN: 1461604 Hom.: 0 Cov.: 31 AF XY: 0.0000248 AC XY: 18 AN XY: 727130

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000671

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000342

Gnomad4 OTH exome AF: 0.0000497

GnomAD4 genome Cov.: 34

Bravo AF: 0.0000151

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Mar 28, 2016

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: LOF variants in this gene are associated with Knobloch syndrome (extreme nearsightedness and skull defect). HGMD associates a missense and a noncoding variant in this gene with increased risk of hepatocellular carcinoma, sporadic breast cancer, and prostate cancer. Endothelin, which results from proteolytic cleavage of COL18A1, is involved in angiogenesis. Because there isn't strong evidence showing that variants in this gene cause hereditary cancer, I am classifying as VUS4 for cancer. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 09, 2021

This sequence change creates a premature translational stop signal (p.Asn24Thrfs*3) in the COL18A1 gene. However, it is currently unclear if variants that occur in this region of the gene cause disease. This variant occurs in alternate transcript NM_030582.3, and corresponds to c.107-12645_107-12644insG in the primary transcript. This variant is present in population databases (rs752078007, gnomAD 0.003%). This variant has not been reported in the literature in individuals affected with COL18A1-related conditions. ClinVar contains an entry for this variant (Variation ID: 402553). 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

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs752078007; hg19: chr21-46875508;