rs752078007

Variant names:

• chr21-45455594-CG-C
• ENST00000355480.10:c.67delG

Your query was ambiguous. Multiple possible variants found:

• chr21-45455594-CG-C
• chr21-45455594-CG-CGG

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PVS1_Strong PM2

The NM_130444.3(COL18A1):​c.67delG​(p.Ala23ProfsTer4) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,604 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: COL18A1 NM_130444.3 frameshift
• Clinical Significance: Not reported in ClinVar
• 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 Likely_pathogenic. Variant got 6 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.
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL18A1	NM_001379500.1	c.107-12645delG		intron_variant	Intron 2 of 41	ENST00000651438.1	NP_001366429.1
COL18A1	NM_130444.3	c.67delG	p.Ala23ProfsTer4	frameshift_variant	Exon 1 of 41		NP_569711.2
COL18A1	NM_030582.4	c.67delG	p.Ala23ProfsTer4	frameshift_variant	Exon 1 of 41		NP_085059.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL18A1	ENST00000355480.10	c.67delG	p.Ala23ProfsTer4	frameshift_variant	Exon 1 of 41	1		ENSP00000347665.5
COL18A1	ENST00000651438.1	c.107-12645delG		intron_variant	Intron 2 of 41		NM_001379500.1	ENSP00000498485.1
COL18A1	ENST00000359759.8	c.67delG	p.Ala23ProfsTer4	frameshift_variant	Exon 1 of 41	5		ENSP00000352798.4

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461604 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727130

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 34

ClinVar

Not reported in ClinVar

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr21-46875508;