rs749009747

Positions:

• chr21-45497644-GC-G
• chr21-45497644-G-GC

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PVS1 PP5_Moderate

The NM_001379500.1(COL18A1):​c.2673del​(p.Gly892AspfsTer17) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000106 in 1,416,192 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: 34)
  • Exomes 𝑓: 0.000011 (0 hom.)
• Consequence: COL18A1 NM_001379500.1 frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: -2.66

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]

SLC19A1 (HGNC:10937): (solute carrier family 19 member 1) The membrane protein encoded by this gene is a transporter of folate and is involved in the regulation of intracellular concentrations of folate. Three transcript variants encoding different isoforms have been found for this gene.[provided by RefSeq, Mar 2011]

ACMG classification

Verdict is Pathogenic. Variant got 10 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PP5: Variant 21-45497644-GC-G is Pathogenic according to our data. Variant chr21-45497644-GC-G is described in ClinVar as [Pathogenic]. Clinvar id is 438062.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr21-45497644-GC-G is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL18A1	NM_001379500.1	c.2673del	p.Gly892AspfsTer17	frameshift_variant	32/42	ENST00000651438.1
COL18A1	NM_130444.3	c.3918del	p.Gly1307AspfsTer17	frameshift_variant	31/41
COL18A1	NM_030582.4	c.3213del	p.Gly1072AspfsTer17	frameshift_variant	31/41

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL18A1	ENST00000651438.1	c.2673del	p.Gly892AspfsTer17	frameshift_variant	32/42		NM_001379500.1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome AF: 0.0000106 AC: 15 AN: 1416192 Hom.: 0 Cov.: 31 AF XY: 0.00000999 AC XY: 7 AN XY: 700440

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000784

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000270

Gnomad4 SAS exome AF: 0.0000248

Gnomad4 FIN exome AF: 0.0000204

Gnomad4 NFE exome AF: 0.00000643

Gnomad4 OTH exome AF: 0.0000170

GnomAD4 genome Cov.: 34

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Apr 07, 2022

ClinVar contains an entry for this variant (Variation ID: 438062). This variant is also known as c.3213delC (p.Gly1072AspfsTer17). This premature translational stop signal has been observed in individual(s) with COL18A1-related conditions (PMID: 32581362). 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 sequence change creates a premature translational stop signal (p.Gly892Aspfs*17) 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). For these reasons, this variant has been classified as Pathogenic. -

Retinal dystrophy Pathogenic:1

Likely pathogenic, no assertion criteria provided

research

NIHR Bioresource Rare Diseases, University of Cambridge

Jan 01, 2015

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs749009747; hg19: chr21-46917558;