rs62000962

Variant names:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001379500.1(COL18A1):c.1981G>A(p.Val661Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.12 in 1,585,750 control chromosomes in the GnomAD database, including 12,184 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.13 ( 1323 hom., cov: 24)

Exomes 𝑓: 0.12 ( 10861 hom. )

Consequence

COL18A1
NM_001379500.1 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: -1.29

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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0025745034).

BP6

Variant 21-45490296-G-A is Benign according to our data. Variant chr21-45490296-G-A is described in ClinVar as [Benign]. Clinvar id is 261897.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr21-45490296-G-A is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.147 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL18A1	NM_001379500.1 link	c.1981G>A	p.Val661Ile	missense_variant	Exon 20 of 42	ENST00000651438.1	NP_001366429.1
COL18A1	NM_130444.3 link	c.3226G>A	p.Val1076Ile	missense_variant	Exon 19 of 41		NP_569711.2	P39060
COL18A1	NM_030582.4 link	c.2521G>A	p.Val841Ile	missense_variant	Exon 19 of 41		NP_085059.2	P39060D3DSM5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
COL18A1	ENST00000651438.1 link	c.1981G>A	p.Val661Ile	missense_variant	Exon 20 of 42		NM_001379500.1	ENSP00000498485.1	P39060-2
COL18A1	ENST00000355480.10 link	c.2521G>A	p.Val841Ile	missense_variant	Exon 19 of 41	1		ENSP00000347665.5	P39060-1
COL18A1	ENST00000359759.8 link	c.3226G>A	p.Val1076Ile	missense_variant	Exon 19 of 41	5		ENSP00000352798.4	P39060-3
COL18A1	ENST00000342220.9 link	c.22G>A	p.Val8Ile	missense_variant	Exon 1 of 23	2		ENSP00000339118.5	H7BXV5

Frequencies

GnomAD3 genomes

AF:

0.128

AC:

19249

AN:

150530

Hom.:

1321

Cov.:

show subpopulations

Gnomad AFR

AF:

0.150

Gnomad AMI

AF:

0.137

Gnomad AMR

AF:

0.0959

Gnomad ASJ

AF:

0.106

Gnomad EAS

AF:

0.0150

Gnomad SAS

AF:

0.147

Gnomad FIN

AF:

0.172

Gnomad MID

AF:

0.0980

Gnomad NFE

AF:

0.123

Gnomad OTH

AF:

0.116

GnomAD3 exomes

AF:

0.116

AC:

23942

AN:

206612

Hom.:

1571

AF XY:

0.119

AC XY:

13272

AN XY:

111888

show subpopulations

Gnomad AFR exome

AF:

0.147

Gnomad AMR exome

AF:

0.0706

Gnomad ASJ exome

AF:

0.112

Gnomad EAS exome

AF:

0.0179

Gnomad SAS exome

AF:

0.152

Gnomad FIN exome

AF:

0.164

Gnomad NFE exome

AF:

0.124

Gnomad OTH exome

AF:

0.117

GnomAD4 exome

AF:

0.120

AC:

171574

AN:

1435110

Hom.:

10861

Cov.:

AF XY:

0.121

AC XY:

85934

AN XY:

711530

show subpopulations

Gnomad4 AFR exome

AF:

0.156

Gnomad4 AMR exome

AF:

0.0740

Gnomad4 ASJ exome

AF:

0.106

Gnomad4 EAS exome

AF:

0.0144

Gnomad4 SAS exome

AF:

0.152

Gnomad4 FIN exome

AF:

0.154

Gnomad4 NFE exome

AF:

0.120

Gnomad4 OTH exome

AF:

0.116

GnomAD4 genome

AF:

0.128

AC:

19272

AN:

150640

Hom.:

1323

Cov.:

AF XY:

0.129

AC XY:

9462

AN XY:

73512

show subpopulations

Gnomad4 AFR

AF:

0.150

Gnomad4 AMR

AF:

0.0954

Gnomad4 ASJ

AF:

0.106

Gnomad4 EAS

AF:

0.0153

Gnomad4 SAS

AF:

0.147

Gnomad4 FIN

AF:

0.172

Gnomad4 NFE

AF:

0.123

Gnomad4 OTH

AF:

0.115

Alfa

AF:

0.119

Hom.:

1198

Bravo

AF:

0.124

TwinsUK

AF:

0.115

AC:

426

ALSPAC

AF:

0.115

AC:

442

ESP6500AA

AF:

0.149

AC:

564

ESP6500EA

AF:

0.112

AC:

918

ExAC

AF:

0.105

AC:

12455

Asia WGS

AF:

0.0840

AC:

293

AN:

3476

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 04, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified

Benign:1

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Knobloch syndrome

Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.078

BayesDel_addAF

Benign

-0.57

BayesDel_noAF

Benign

-0.46

CADD

Benign

0.42

DANN

Benign

0.70

DEOGEN2

Benign

0.23

.;.;T;T

Eigen

Benign

-1.4

Eigen_PC

Benign

-1.4

FATHMM_MKL

Benign

0.079

LIST_S2

Uncertain

0.87

D;D;D;D

MetaRNN

Benign

0.0026

T;T;T;T

MetaSVM

Benign

-0.86

MutationAssessor

Benign

0.050

.;.;N;.

PrimateAI

Benign

0.44

PROVEAN

Benign

-0.45

N;N;N;N

REVEL

Benign

0.11

Sift

Benign

0.42

T;T;T;T

Sift4G

Benign

0.43

T;T;T;T

Polyphen

0.016

B;B;B;.

Vest4

0.076

MPC

0.063

ClinPred

0.00058

GERP RS

-2.5

RBP_binding_hub_radar

1.1

RBP_regulation_power_radar

2.2

Varity_R

0.011

gMVP

0.069

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

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