Genetic Variant NM_001379500.1:c.1791_1808delTGGGCCCCCTGGGCCCCC (chr21-45486944-CCCCCCTGGGCCCCCTGGG-C) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM4

The NM_001379500.1(COL18A1):c.1791_1808delTGGGCCCCCTGGGCCCCC(p.Gly598_Pro603del) variant causes a disruptive inframe deletion change. The variant allele was found at a frequency of 0.000000749 in 1,334,512 control chromosomes in the GnomAD database, with no homozygous occurrence. It is difficult to determine the true allele frequency of this variant because it is of type DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 7.5e-7 ( 0 hom. )

Consequence

COL18A1
NM_001379500.1 disruptive_inframe_deletion

Scores

Not classified

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 4.83

Publications

0 publications found

Variant links:

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]

COL18A1 Gene-Disease associations (from GenCC):

Knobloch syndrome 1
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: ClinGen, G2P, Labcorp Genetics (formerly Invitae)
Knobloch syndrome
Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Laboratory for Molecular Medicine, Orphanet
hereditary glaucoma, primary closed-angle
Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

COL18A1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM4

Nonframeshift variant in NON repetitive region in NM_001379500.1.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001379500.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
COL18A1	NM_001379500.1	MANE Select	c.1791_1808delTGGGCCCCCTGGGCCCCC	p.Gly598_Pro603del	disruptive_inframe_deletion	Exon 16 of 42	NP_001366429.1	P39060-2
COL18A1	NM_130444.3		c.3036_3053delTGGGCCCCCTGGGCCCCC	p.Gly1013_Pro1018del	disruptive_inframe_deletion	Exon 15 of 41	NP_569711.2
COL18A1	NM_030582.4		c.2331_2348delTGGGCCCCCTGGGCCCCC	p.Gly778_Pro783del	disruptive_inframe_deletion	Exon 15 of 41	NP_085059.2	A0AAG2UXZ5

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
COL18A1	ENST00000651438.1	MANE Select	c.1791_1808delTGGGCCCCCTGGGCCCCC	p.Gly598_Pro603del	disruptive_inframe_deletion	Exon 16 of 42	ENSP00000498485.1	P39060-2
COL18A1	ENST00000355480.10	TSL:1	c.2331_2348delTGGGCCCCCTGGGCCCCC	p.Gly778_Pro783del	disruptive_inframe_deletion	Exon 15 of 41	ENSP00000347665.5	P39060-1
COL18A1	ENST00000359759.8	TSL:5	c.3036_3053delTGGGCCCCCTGGGCCCCC	p.Gly1013_Pro1018del	disruptive_inframe_deletion	Exon 15 of 41	ENSP00000352798.4	P39060-3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.49e-7

AC:

AN:

1334512

Hom.:

AF XY:

0.00

AC XY:

AN XY:

656314

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

28982

American (AMR)

AF:

0.00

AC:

AN:

27314

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

21576

East Asian (EAS)

AF:

0.0000289

AC:

AN:

34614

South Asian (SAS)

AF:

0.00

AC:

AN:

72124

European-Finnish (FIN)

AF:

0.00

AC:

AN:

42034

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3780

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1048922

Other (OTH)

AF:

0.00

AC:

AN:

55166

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.575

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

4.8

Splicing

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over