rs114139997

Positions:

chr21-45455861-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The ENST00000355480.10(COL18A1):c.331G>A(p.Gly111Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000916 in 1,613,116 control chromosomes in the GnomAD database, including 11 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

Frequency

Genomes: 𝑓 0.0051 ( 7 hom., cov: 33)

Exomes 𝑓: 0.00048 ( 4 hom. )

Consequence

COL18A1
ENST00000355480.10 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 1.32

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=0.010848165).

BP6

Variant 21-45455861-G-A is Benign according to our data. Variant chr21-45455861-G-A is described in ClinVar as [Benign]. Clinvar id is 447126.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00507 (772/152264) while in subpopulation AFR AF= 0.018 (749/41544). AF 95% confidence interval is 0.017. There are 7 homozygotes in gnomad4. There are 367 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 7 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
COL18A1	NM_001379500.1 linkuse as main transcript	c.107-12381G>A		intron_variant		ENST00000651438.1	NP_001366429.1
COL18A1	NM_130444.3 linkuse as main transcript	c.331G>A	p.Gly111Arg	missense_variant	1/41		NP_569711.2
COL18A1	NM_030582.4 linkuse as main transcript	c.331G>A	p.Gly111Arg	missense_variant	1/41		NP_085059.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COL18A1	ENST00000355480.10 linkuse as main transcript	c.331G>A	p.Gly111Arg	missense_variant	1/41	1		ENSP00000347665		P39060-1
COL18A1	ENST00000651438.1 linkuse as main transcript	c.107-12381G>A		intron_variant			NM_001379500.1	ENSP00000498485		P39060-2
COL18A1	ENST00000359759.8 linkuse as main transcript	c.331G>A	p.Gly111Arg	missense_variant	1/41	5		ENSP00000352798	P1	P39060-3

Frequencies

GnomAD3 genomes

AF:

0.00507

AC:

772

AN:

152146

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0181

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00118

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:

0.0000147

Gnomad OTH

AF:

0.00144

GnomAD3 exomes

AF:

0.00123

AC:

304

AN:

247408

Hom.:

AF XY:

0.000913

AC XY:

123

AN XY:

134746

show subpopulations

Gnomad AFR exome

AF:

0.0187

Gnomad AMR exome

AF:

0.000493

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000179

Gnomad OTH exome

AF:

0.000332

GnomAD4 exome

AF:

0.000483

AC:

705

AN:

1460852

Hom.:

Cov.:

AF XY:

0.000405

AC XY:

294

AN XY:

726752

show subpopulations

Gnomad4 AFR exome

AF:

0.0182

Gnomad4 AMR exome

AF:

0.000514

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000232

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000126

Gnomad4 OTH exome

AF:

0.000861

GnomAD4 genome

AF:

0.00507

AC:

772

AN:

152264

Hom.:

Cov.:

AF XY:

0.00493

AC XY:

367

AN XY:

74450

show subpopulations

Gnomad4 AFR

AF:

0.0180

Gnomad4 AMR

AF:

0.00118

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00142

Alfa

AF:

0.00102

Hom.:

Bravo

AF:

0.00574

ESP6500AA

AF:

0.0188

AC:

ESP6500EA

AF:

0.000118

AC:

ExAC

AF:

0.00167

AC:

202

Asia WGS

AF:

0.000866

AC:

AN:

3478

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 27, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

Athena Diagnostics

Sep 20, 2016

- -

COL18A1-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

May 08, 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). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.57

BayesDel_addAF

Benign

-0.39

BayesDel_noAF

Benign

-0.32

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.14

.;T

Eigen

Uncertain

0.21

Eigen_PC

Benign

0.11

FATHMM_MKL

Benign

0.71

LIST_S2

Benign

0.73

T;T

MetaRNN

Benign

0.011

T;T

MetaSVM

Benign

-0.73

MutationTaster

Benign

1.0

D;N;N

PrimateAI

Uncertain

0.51

PROVEAN

Uncertain

-3.6

D;D

REVEL

Uncertain

0.35

Sift

Pathogenic

0.0

D;D

Sift4G

Pathogenic

0.0

D;D

Polyphen

0.97

D;D

Vest4

0.33

MutPred

0.84

Loss of helix (P = 0.0167);Loss of helix (P = 0.0167);

MVP

0.73

MPC

0.080

ClinPred

0.054

GERP RS

3.7

Varity_R

0.55

gMVP

0.19

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