21-45477808-GC-G

Position:

• chr21-45477808-GC-G

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_001379500.1(COL18A1):​c.1070delC​(p.Pro357fs) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000143 in 1,398,278 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: COL18A1 NM_001379500.1 frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: -1.71

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 Pathogenic. Variant got 12 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 21-45477808-GC-G is Pathogenic according to our data. Variant chr21-45477808-GC-G is described in ClinVar as [Pathogenic]. Clinvar id is 1442812.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COL18A1	NM_001379500.1	c.1070delC	p.Pro357fs	frameshift_variant	8/42	ENST00000651438.1	NP_001366429.1
COL18A1	NM_130444.3	c.2315delC	p.Pro772fs	frameshift_variant	7/41		NP_569711.2
COL18A1	NM_030582.4	c.1610delC	p.Pro537fs	frameshift_variant	7/41		NP_085059.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COL18A1	ENST00000651438.1	c.1070delC	p.Pro357fs	frameshift_variant	8/42		NM_001379500.1	ENSP00000498485.1
COL18A1	ENST00000355480.10	c.1610delC	p.Pro537fs	frameshift_variant	7/41	1		ENSP00000347665.5
COL18A1	ENST00000359759.8	c.2315delC	p.Pro772fs	frameshift_variant	7/41	5		ENSP00000352798.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000143 AC: 2 AN: 1398278 Hom.: 0 Cov.: 33 AF XY: 0.00000145 AC XY: 1 AN XY: 689744

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000126

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.27e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Aug 28, 2021

For these reasons, this variant has been classified as Pathogenic. This variant has been observed in individual(s) with Knobloch syndrome (PMID: 32178553). This variant is also known as c.1610del (p.Pro537Glnfs*16). This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Pro357Glnfs*16) in the COL18A1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in COL18A1 are known to be pathogenic (PMID: 12415512, 25456301). -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr21-46897722;