rs200284308

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_StrongBP6

The NM_130444.3(COL18A1):​c.515G>A​(p.Arg172His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000927 in 1,607,990 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R172C) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00060 ( 0 hom., cov: 33)
Exomes 𝑓: 0.00096 ( 1 hom. )

Consequence

COL18A1
NM_130444.3 missense

Scores

18

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5B:4

Conservation

PhyloP100: 0.274
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]

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -5 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.0149638355).
BP6
Variant 21-45456045-G-A is Benign according to our data. Variant chr21-45456045-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 447131.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=4, Likely_benign=2}. Variant chr21-45456045-G-A is described in Lovd as [Likely_benign].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
COL18A1NM_001379500.1 linkc.107-12197G>A intron_variant Intron 2 of 41 ENST00000651438.1 NP_001366429.1
COL18A1NM_130444.3 linkc.515G>A p.Arg172His missense_variant Exon 1 of 41 NP_569711.2 P39060
COL18A1NM_030582.4 linkc.515G>A p.Arg172His missense_variant Exon 1 of 41 NP_085059.2 P39060D3DSM5

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
COL18A1ENST00000355480.10 linkc.515G>A p.Arg172His missense_variant Exon 1 of 41 1 ENSP00000347665.5 P39060-1
COL18A1ENST00000651438.1 linkc.107-12197G>A intron_variant Intron 2 of 41 NM_001379500.1 ENSP00000498485.1 P39060-2
COL18A1ENST00000359759.8 linkc.515G>A p.Arg172His missense_variant Exon 1 of 41 5 ENSP00000352798.4 P39060-3

Frequencies

GnomAD3 genomes
AF:
0.000605
AC:
92
AN:
152108
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.000241
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000393
Gnomad ASJ
AF:
0.000289
Gnomad EAS
AF:
0.000193
Gnomad SAS
AF:
0.000207
Gnomad FIN
AF:
0.000283
Gnomad MID
AF:
0.00316
Gnomad NFE
AF:
0.00100
Gnomad OTH
AF:
0.000478
GnomAD2 exomes
AF:
0.000439
AC:
108
AN:
245960
AF XY:
0.000462
show subpopulations
Gnomad AFR exome
AF:
0.0000664
Gnomad AMR exome
AF:
0.000175
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.000376
Gnomad NFE exome
AF:
0.000820
Gnomad OTH exome
AF:
0.000334
GnomAD4 exome
AF:
0.000961
AC:
1399
AN:
1455764
Hom.:
1
Cov.:
71
AF XY:
0.000966
AC XY:
699
AN XY:
723238
show subpopulations
Gnomad4 AFR exome
AF:
0.000240
AC:
8
AN:
33320
Gnomad4 AMR exome
AF:
0.000179
AC:
8
AN:
44574
Gnomad4 ASJ exome
AF:
0.00
AC:
0
AN:
25982
Gnomad4 EAS exome
AF:
0.0000253
AC:
1
AN:
39592
Gnomad4 SAS exome
AF:
0.0000116
AC:
1
AN:
86200
Gnomad4 FIN exome
AF:
0.000230
AC:
12
AN:
52096
Gnomad4 NFE exome
AF:
0.00121
AC:
1340
AN:
1108134
Gnomad4 Remaining exome
AF:
0.000482
AC:
29
AN:
60110
Heterozygous variant carriers
0
88
175
263
350
438
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
Exome Het
Variant carriers
0
54
108
162
216
270
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
GnomAD4 genome
AF:
0.000604
AC:
92
AN:
152226
Hom.:
0
Cov.:
33
AF XY:
0.000524
AC XY:
39
AN XY:
74428
show subpopulations
Gnomad4 AFR
AF:
0.000241
AC:
0.000240709
AN:
0.000240709
Gnomad4 AMR
AF:
0.000392
AC:
0.000392157
AN:
0.000392157
Gnomad4 ASJ
AF:
0.000289
AC:
0.000288517
AN:
0.000288517
Gnomad4 EAS
AF:
0.000193
AC:
0.000193125
AN:
0.000193125
Gnomad4 SAS
AF:
0.000207
AC:
0.000207383
AN:
0.000207383
Gnomad4 FIN
AF:
0.000283
AC:
0.000282592
AN:
0.000282592
Gnomad4 NFE
AF:
0.00100
AC:
0.00100026
AN:
0.00100026
Gnomad4 OTH
AF:
0.000473
AC:
0.000473485
AN:
0.000473485
Heterozygous variant carriers
0
6
12
18
24
30
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
Genome Het
Variant carriers
0
2
4
6
8
10
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
Alfa
AF:
0.000893
Hom.:
0
Bravo
AF:
0.000495
TwinsUK
AF:
0.000809
AC:
3
ALSPAC
AF:
0.000259
AC:
1
ESP6500AA
AF:
0.000506
AC:
2
ESP6500EA
AF:
0.000360
AC:
3
ExAC
AF:
0.000496
AC:
60
Asia WGS
AF:
0.000866
AC:
3
AN:
3478
EpiCase
AF:
0.000709
EpiControl
AF:
0.000593

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:5Benign:4
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not provided Uncertain:2Benign:3
-
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)
Significance:Likely benign
Review Status:no assertion criteria provided
Collection Method:clinical testing

- -

Aug 01, 2017
GeneDx
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

The R172H variant in the COL18A1 gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. This variant is only present in a single alternate transcript of the COL18A1 gene (NM_030582.3), but not in any other known transcript, including the primary isoform used by the Human Gene Mutation database (NM_130445.3). Although not present in the homozygous state, the R172H variant is observed in 53/63514 (0.083%) alleles from individuals of non-Finnish European background in the ExAC dataset (Lek et al., 2016). The R172H variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position that is not conserved. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. We interpret R172H as a variant of uncertain significance. -

-
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center
Significance:Likely benign
Review Status:no assertion criteria provided
Collection Method:clinical testing

- -

Oct 24, 2022
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

The COL18A1 gene has multiple clinically relevant transcripts. This variant occurs in alternate transcript NM_030582.4, and corresponds to NM_130445.2:c.107-12197G>A in the primary transcript. This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 172 of the COL18A1 protein (p.Arg172His). This variant is present in population databases (rs200284308, gnomAD 0.09%), and has an allele count higher than expected for a pathogenic variant. This variant has not been reported in the literature in individuals affected with COL18A1-related conditions. ClinVar contains an entry for this variant (Variation ID: 447131). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Not Available"; Align-GVGD: "Not Available". The histidine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant is not likely to affect RNA splicing. 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. -

Mar 01, 2024
CeGaT Center for Human Genetics Tuebingen
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

COL18A1: BP4 -

not specified Uncertain:1
Jan 25, 2017
Athena Diagnostics
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

COL18A1-related disorder Uncertain:1
Jul 09, 2024
PreventionGenetics, part of Exact Sciences
Significance:Uncertain significance
Review Status:no assertion criteria provided
Collection Method:clinical testing

The COL18A1 c.515G>A variant is predicted to result in the amino acid substitution p.Arg172His. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.090% of alleles in individuals of European (Non-Finnish) descent in gnomAD, which is likely too frequent for an unreported disease-causing variant. Although we suspect that this variant may be benign, at this time, the clinical significance is uncertain due to the absence of conclusive functional and genetic evidence. -

Knobloch syndrome Uncertain:1
Oct 31, 2018
Fulgent Genetics, Fulgent Genetics
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Inborn genetic diseases Benign:1
Jan 21, 2025
Ambry Genetics
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.073
BayesDel_addAF
Benign
-0.69
T
BayesDel_noAF
Benign
-0.80
CADD
Benign
3.3
DANN
Benign
0.88
DEOGEN2
Benign
0.023
.;T
Eigen
Benign
-1.5
Eigen_PC
Benign
-1.5
FATHMM_MKL
Benign
0.034
N
LIST_S2
Benign
0.45
T;T
M_CAP
Benign
0.039
D
MetaRNN
Benign
0.015
T;T
MetaSVM
Benign
-1.0
T
PrimateAI
Benign
0.26
T
PROVEAN
Benign
-1.1
N;N
REVEL
Benign
0.019
Sift
Benign
0.12
T;T
Sift4G
Benign
0.23
T;T
Polyphen
0.0010
B;B
Vest4
0.045
MVP
0.15
MPC
0.082
ClinPred
0.034
T
GERP RS
-2.7
Varity_R
0.028
gMVP
0.077
Mutation Taster
=100/0
polymorphism

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.

Other links and lift over

dbSNP: rs200284308; hg19: chr21-46875959; API