21-45476389-C-A

Position:

chr21-45476389-C-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_001379500.1(COL18A1):c.837C>A(p.Pro279Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00092 in 1,613,728 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. P279P) has been classified as Benign.

Frequency

Genomes: 𝑓 0.0049 ( 2 hom., cov: 34)

Exomes 𝑓: 0.00051 ( 3 hom. )

Consequence

COL18A1
NM_001379500.1 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: -4.84

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 Benign. Variant got -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.67).

BP6

Variant 21-45476389-C-A is Benign according to our data. Variant chr21-45476389-C-A is described in ClinVar as [Benign]. Clinvar id is 895071.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr21-45476389-C-A is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=-4.84 with no splicing effect.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00487 (741/152110) while in subpopulation AFR AF= 0.0168 (696/41410). AF 95% confidence interval is 0.0158. There are 2 homozygotes in gnomad4. There are 364 alleles in male gnomad4 subpopulation. Median coverage is 34. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 2 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COL18A1	NM_001379500.1 linkuse as main transcript	c.837C>A	p.Pro279Pro	synonymous_variant	6/42	ENST00000651438.1	NP_001366429.1
COL18A1	NM_130444.3 linkuse as main transcript	c.2082C>A	p.Pro694Pro	synonymous_variant	5/41		NP_569711.2	P39060
COL18A1	NM_030582.4 linkuse as main transcript	c.1377C>A	p.Pro459Pro	synonymous_variant	5/41		NP_085059.2	P39060D3DSM5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
COL18A1	ENST00000651438.1 linkuse as main transcript	c.837C>A	p.Pro279Pro	synonymous_variant	6/42		NM_001379500.1	ENSP00000498485.1	P39060-2
COL18A1	ENST00000355480.10 linkuse as main transcript	c.1377C>A	p.Pro459Pro	synonymous_variant	5/41	1		ENSP00000347665.5	P39060-1
COL18A1	ENST00000359759.8 linkuse as main transcript	c.2082C>A	p.Pro694Pro	synonymous_variant	5/41	5		ENSP00000352798.4	P39060-3

Frequencies

GnomAD3 genomes

AF:

0.00487

AC:

740

AN:

151990

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0168

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00223

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00384

GnomAD3 exomes

AF:

0.00117

AC:

290

AN:

247204

Hom.:

AF XY:

0.000817

AC XY:

110

AN XY:

134568

show subpopulations

Gnomad AFR exome

AF:

0.0167

Gnomad AMR exome

AF:

0.000786

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000655

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000447

Gnomad OTH exome

AF:

0.000500

GnomAD4 exome

AF:

0.000508

AC:

743

AN:

1461618

Hom.:

Cov.:

AF XY:

0.000425

AC XY:

309

AN XY:

727094

show subpopulations

Gnomad4 AFR exome

AF:

0.0186

Gnomad4 AMR exome

AF:

0.000806

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000580

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000630

Gnomad4 OTH exome

AF:

0.00106

GnomAD4 genome

AF:

0.00487

AC:

741

AN:

152110

Hom.:

Cov.:

AF XY:

0.00489

AC XY:

364

AN XY:

74384

show subpopulations

Gnomad4 AFR

AF:

0.0168

Gnomad4 AMR

AF:

0.00222

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00380

Alfa

AF:

0.000248

Hom.:

141

EpiCase

AF:

0.00

EpiControl

AF:

0.000119

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Jan 18, 2019

- -

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 30, 2024

- -

COL18A1-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 22, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Knobloch syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.67

CADD

Benign

0.014

DANN

Benign

0.36

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

Details are displayed if max score is > 0.2

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