rs764710670

Positions:

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM4BP6BS2

The NM_001379500.1(COL18A1):c.1800_1808delTGGGCCCCC(p.Gly601_Pro603del) variant causes a disruptive inframe deletion change. The variant allele was found at a frequency of 0.000531 in 1,486,532 control chromosomes in the GnomAD database, including 5 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00098 ( 1 hom., cov: 33)

Exomes 𝑓: 0.00048 ( 4 hom. )

Consequence

COL18A1
NM_001379500.1 disruptive_inframe_deletion

Scores

Not classified

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:2

Conservation

PhyloP100: 4.83

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -3 ACMG points.

PM4

Nonframeshift variant in NON repetitive region in NM_001379500.1.

BP6

Variant 21-45486944-CCCCCCTGGG-C is Benign according to our data. Variant chr21-45486944-CCCCCCTGGG-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 447115.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=1}. Variant chr21-45486944-CCCCCCTGGG-C is described in Lovd as [Likely_benign]. Variant chr21-45486944-CCCCCCTGGG-C is described in Lovd as [Likely_benign].

BS2

High Homozygotes in GnomAdExome4 at 4 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COL18A1	NM_001379500.1 linkuse as main transcript	c.1800_1808delTGGGCCCCC	p.Gly601_Pro603del	disruptive_inframe_deletion	16/42	ENST00000651438.1	NP_001366429.1
COL18A1	NM_130444.3 linkuse as main transcript	c.3045_3053delTGGGCCCCC	p.Gly1016_Pro1018del	disruptive_inframe_deletion	15/41		NP_569711.2	P39060
COL18A1	NM_030582.4 linkuse as main transcript	c.2340_2348delTGGGCCCCC	p.Gly781_Pro783del	disruptive_inframe_deletion	15/41		NP_085059.2	P39060D3DSM5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
COL18A1	ENST00000651438.1 linkuse as main transcript	c.1800_1808delTGGGCCCCC	p.Gly601_Pro603del	disruptive_inframe_deletion	16/42		NM_001379500.1	ENSP00000498485.1	P39060-2
COL18A1	ENST00000355480.10 linkuse as main transcript	c.2340_2348delTGGGCCCCC	p.Gly781_Pro783del	disruptive_inframe_deletion	15/41	1		ENSP00000347665.5	P39060-1
COL18A1	ENST00000359759.8 linkuse as main transcript	c.3045_3053delTGGGCCCCC	p.Gly1016_Pro1018del	disruptive_inframe_deletion	15/41	5		ENSP00000352798.4	P39060-3

Frequencies

GnomAD3 genomes

AF:

0.000967

AC:

147

AN:

151956

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00218

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000327

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.00507

Gnomad SAS

AF:

0.000621

Gnomad FIN

AF:

0.000377

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000221

Gnomad OTH

AF:

0.00144

GnomAD3 exomes

AF:

0.000766

AC:

AN:

107000

Hom.:

AF XY:

0.000735

AC XY:

AN XY:

58514

show subpopulations

Gnomad AFR exome

AF:

0.00186

Gnomad AMR exome

AF:

0.000232

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00615

Gnomad SAS exome

AF:

0.000130

Gnomad FIN exome

AF:

0.000331

Gnomad NFE exome

AF:

0.000141

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000480

AC:

641

AN:

1334458

Hom.:

AF XY:

0.000468

AC XY:

307

AN XY:

656280

show subpopulations

Gnomad4 AFR exome

AF:

0.00228

Gnomad4 AMR exome

AF:

0.000256

Gnomad4 ASJ exome

AF:

0.0000927

Gnomad4 EAS exome

AF:

0.00714

Gnomad4 SAS exome

AF:

0.000360

Gnomad4 FIN exome

AF:

0.000428

Gnomad4 NFE exome

AF:

0.000235

Gnomad4 OTH exome

AF:

0.000508

GnomAD4 genome

AF:

0.000980

AC:

149

AN:

152074

Hom.:

Cov.:

AF XY:

0.00113

AC XY:

AN XY:

74352

show subpopulations

Gnomad4 AFR

AF:

0.00224

Gnomad4 AMR

AF:

0.000327

Gnomad4 ASJ

AF:

0.000288

Gnomad4 EAS

AF:

0.00488

Gnomad4 SAS

AF:

0.000622

Gnomad4 FIN

AF:

0.000377

Gnomad4 NFE

AF:

0.000221

Gnomad4 OTH

AF:

0.00142

Bravo

AF:

0.00114

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Uncertain:1Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jun 12, 2024	Variant summary: COL18A1 c.1800_1808delTGGGCCCCC (p.Pro603_Pro605del) results in an in-frame deletion in a repetitive region removing 3 amino acids (i.e. one Pro-Gly-Pro unit) from four consecutive PGP repeats. The variant allele was found at a frequency of 0.00053 in 1,486,532 control chromosomes in the gnomAD database (v4.1 dataset) including 5 homozygotes, and was predominantly reported within the East Asian subpopulation at a frequency of 0.0068. In addition, the variant was reported with similarly high allele frequency (0.0055) in Chinese control individuals (ChinaMAP database [PMID: 32355288]; zygosity is not specified in this dataset). To our knowledge, no occurrence of c.1800_1808delTGGGCCCCC in individuals affected with Knobloch Syndrome 1 and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 447115). Based on the evidence outlined above, the variant was classified as likely benign. -
Uncertain significance, criteria provided, single submitter	clinical testing	Athena Diagnostics	Oct 17, 2016	- -

not provided

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 14, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Splicing

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over