rs201006742

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4_StrongBP6

The NM_001379500.1(COL18A1):c.3665G>A(p.Arg1222His) variant causes a missense change. The variant allele was found at a frequency of 0.000705 in 1,606,156 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts 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. R1222C) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0018 ( 0 hom., cov: 34)

Exomes 𝑓: 0.00059 ( 1 hom. )

Consequence

COL18A1
NM_001379500.1 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:3

Conservation

PhyloP100: 6.53

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:

SLC19A1 (HGNC:10937): (solute carrier family 19 member 1) The membrane protein encoded by this gene is a transporter of folate and is involved in the regulation of intracellular concentrations of folate. Three transcript variants encoding different isoforms have been found for this gene.[provided by RefSeq, Mar 2011]

SLC19A1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -5 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.014780968).

BP6

Variant 21-45510233-G-A is Benign according to our data. Variant chr21-45510233-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 447129.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Benign=1, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL18A1	NM_001379500.1 linkuse as main transcript	c.3665G>A	p.Arg1222His	missense_variant	40/42	ENST00000651438.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL18A1	ENST00000651438.1 linkuse as main transcript	c.3665G>A	p.Arg1222His	missense_variant	40/42		NM_001379500.1		P39060-2

Frequencies

GnomAD3 genomes

AF:

0.00182

AC:

277

AN:

152198

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00560

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000981

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000377

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.000338

Gnomad OTH

AF:

0.000958

GnomAD3 exomes

AF:

0.000654

AC:

149

AN:

227788

Hom.:

AF XY:

0.000541

AC XY:

AN XY:

125674

show subpopulations

Gnomad AFR exome

AF:

0.00588

Gnomad AMR exome

AF:

0.000269

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000688

Gnomad FIN exome

AF:

0.000563

Gnomad NFE exome

AF:

0.000458

Gnomad OTH exome

AF:

0.000882

GnomAD4 exome

AF:

0.000588

AC:

855

AN:

1453840

Hom.:

Cov.:

AF XY:

0.000527

AC XY:

381

AN XY:

722852

show subpopulations

Gnomad4 AFR exome

AF:

0.00580

Gnomad4 AMR exome

AF:

0.000408

Gnomad4 ASJ exome

AF:

0.0000385

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000705

Gnomad4 FIN exome

AF:

0.000894

Gnomad4 NFE exome

AF:

0.000489

Gnomad4 OTH exome

AF:

0.000800

GnomAD4 genome

AF:

0.00183

AC:

278

AN:

152316

Hom.:

Cov.:

AF XY:

0.00162

AC XY:

121

AN XY:

74478

show subpopulations

Gnomad4 AFR

AF:

0.00561

Gnomad4 AMR

AF:

0.000979

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000377

Gnomad4 NFE

AF:

0.000338

Gnomad4 OTH

AF:

0.000948

Alfa

AF:

0.000868

Hom.:

Bravo

AF:

0.00223

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.00343

AC:

ESP6500EA

AF:

0.000241

AC:

ExAC

AF:

0.000827

AC:

Asia WGS

AF:

0.000577

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:1

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Apr 12, 2022	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Athena Diagnostics

Aug 22, 2016

- -

COL18A1-related condition

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 24, 2020

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

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.71

BayesDel_addAF

Benign

-0.21

BayesDel_noAF

Uncertain

-0.080

Cadd

Uncertain

Dann

Pathogenic

1.0

Eigen

Pathogenic

0.69

Eigen_PC

Uncertain

0.56

FATHMM_MKL

Uncertain

0.89

LIST_S2

Uncertain

0.97

D;D;D;D

M_CAP

Uncertain

0.18

MetaRNN

Benign

0.015

T;T;T;T

MetaSVM

Uncertain

0.0055

MutationTaster

Benign

1.0

D;D;D;D

PrimateAI

Uncertain

0.74

PROVEAN

Uncertain

-4.0

D;D;D;D

REVEL

Uncertain

0.50

Sift

Pathogenic

0.0

D;T;D;D

Sift4G

Uncertain

0.0020

D;D;D;D

Polyphen

1.0

D;D;D;.

Vest4

0.60

MVP

0.71

MPC

0.45

ClinPred

0.061

GERP RS

4.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.2

Varity_R

0.57

gMVP

0.76

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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