21-45480096-G-GCCCCCAGGA

Position:

• chr21-45480096-G-GCCCCCAGGA

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM4

The NM_001379500.1(COL18A1):​c.1343_1351dup​(p.Pro448_Pro450dup) variant causes a inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0013 in 1,608,150 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.00090 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0013 (0 hom.)
• Consequence: COL18A1 NM_001379500.1 inframe_insertion
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 0.503

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 2 ACMG points.

• PM4: Nonframeshift variant in NON repetitive region in NM_001379500.1.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COL18A1	NM_001379500.1	c.1343_1351dup	p.Pro448_Pro450dup	inframe_insertion	11/42	ENST00000651438.1	NP_001366429.1
COL18A1	NM_030582.4	c.1883_1891dup	p.Pro628_Pro630dup	inframe_insertion	10/41		NP_085059.2
COL18A1	NM_130444.3	c.2588_2596dup	p.Pro863_Pro865dup	inframe_insertion	10/41		NP_569711.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COL18A1	ENST00000651438.1	c.1343_1351dup	p.Pro448_Pro450dup	inframe_insertion	11/42		NM_001379500.1	ENSP00000498485
COL18A1	ENST00000355480.10	c.1883_1891dup	p.Pro628_Pro630dup	inframe_insertion	10/41	1		ENSP00000347665
COL18A1	ENST00000359759.8	c.2588_2596dup	p.Pro863_Pro865dup	inframe_insertion	10/41	5		ENSP00000352798	P1

Frequencies

GnomAD3 genomes AF: 0.000903 AC: 137 AN: 151796 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000145

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000459

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000945

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00181

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000474 AC: 117 AN: 246620 Hom.: 0 AF XY: 0.000425 AC XY: 57 AN XY: 134120

Gnomad AFR exome AF: 0.0000648

Gnomad AMR exome AF: 0.000203

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: 0.000923

Gnomad OTH exome AF: 0.00116

GnomAD4 exome AF: 0.00134 AC: 1946 AN: 1456236 Hom.: 0 Cov.: 31 AF XY: 0.00126 AC XY: 914 AN XY: 724834

Gnomad4 AFR exome AF: 0.000150

Gnomad4 AMR exome AF: 0.000268

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000188

Gnomad4 NFE exome AF: 0.00163

Gnomad4 OTH exome AF: 0.00206

GnomAD4 genome AF: 0.000902 AC: 137 AN: 151914 Hom.: 0 Cov.: 32 AF XY: 0.000701 AC XY: 52 AN XY: 74230

Gnomad4 AFR AF: 0.000145

Gnomad4 AMR AF: 0.000458

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000945

Gnomad4 NFE AF: 0.00181

Gnomad4 OTH AF: 0.00

Alfa AF: 0.00135 Hom.: 0

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

Athena Diagnostics

Oct 18, 2016

- -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 01, 2022

This variant, c.1343_1351dup, results in the insertion of 3 amino acid(s) of the COL18A1 protein (p.Pro448_Pro450dup), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs775305174, gnomAD 0.1%), and has an allele count higher than expected for a pathogenic variant. 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: 447113). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. 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

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

Publications

LitVar

Other links and lift over

dbSNP: rs775305174; hg19: chr21-46900010;