21-45486944-CCCCCCTGGGCCCCCTGGG-CCCCCCTGGGCCCCCTGGGCCCCCTGGG

Variant names:

• chr21-45486944-C-CCCCCCTGGG
• rs764710670
• NM_001379500.1:c.1800_1808dupTGGGCCCCC

Variant summary

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

The NM_001379500.1(COL18A1):​c.1800_1808dupTGGGCCCCC​(p.Pro603_Gly604insGlyProPro) variant causes a disruptive inframe insertion change. The variant allele was found at a frequency of 0.0000451 in 1,486,468 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000049 (0 hom.)
• Consequence: COL18A1 NM_001379500.1 disruptive_inframe_insertion
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.80

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 rank	MANE	Protein	UniProt
COL18A1	NM_001379500.1	c.1800_1808dupTGGGCCCCC	p.Pro603_Gly604insGlyProPro	disruptive_inframe_insertion	Exon 16 of 42	ENST00000651438.1	NP_001366429.1
COL18A1	NM_130444.3	c.3045_3053dupTGGGCCCCC	p.Pro1018_Gly1019insGlyProPro	disruptive_inframe_insertion	Exon 15 of 41		NP_569711.2
COL18A1	NM_030582.4	c.2340_2348dupTGGGCCCCC	p.Pro783_Gly784insGlyProPro	disruptive_inframe_insertion	Exon 15 of 41		NP_085059.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL18A1	ENST00000651438.1	c.1800_1808dupTGGGCCCCC	p.Pro603_Gly604insGlyProPro	disruptive_inframe_insertion	Exon 16 of 42		NM_001379500.1	ENSP00000498485.1
COL18A1	ENST00000355480.10	c.2340_2348dupTGGGCCCCC	p.Pro783_Gly784insGlyProPro	disruptive_inframe_insertion	Exon 15 of 41	1		ENSP00000347665.5
COL18A1	ENST00000359759.8	c.3045_3053dupTGGGCCCCC	p.Pro1018_Gly1019insGlyProPro	disruptive_inframe_insertion	Exon 15 of 41	5		ENSP00000352798.4

Frequencies

GnomAD3 genomes AF: 0.0000132 AC: 2 AN: 151956 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.0000654 AC: 7 AN: 107000 Hom.: 0 AF XY: 0.0000342 AC XY: 2 AN XY: 58514

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000116

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000650

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000942

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000487 AC: 65 AN: 1334512 Hom.: 0 Cov.: 30 AF XY: 0.0000488 AC XY: 32 AN XY: 656314

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000732

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000832

Gnomad4 FIN exome AF: 0.0000238

Gnomad4 NFE exome AF: 0.0000419

Gnomad4 OTH exome AF: 0.000218

GnomAD4 genome AF: 0.0000132 AC: 2 AN: 151956 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 74224

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.000478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Sep 27, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant, c.1800_1808dup, results in the insertion of 3 amino acid(s) of the COL18A1 protein (p.Pro603_Pro605dup), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs776078381, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with COL18A1-related conditions. 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: rs764710670; hg19: chr21-46906858;