chr21-45477816-G-C

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 0P and 0B.

The NM_001379500.1(COL18A1):c.1072G>C(p.Gly358Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000516 in 1,551,570 control chromosomes in the GnomAD database, with no homozygous occurrence. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000043 ( 0 hom. )

Consequence

COL18A1
NM_001379500.1 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 2.51

Publications

2 publications found

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 Gene-Disease associations (from GenCC):

Knobloch syndrome 1
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, G2P
Knobloch syndrome
Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Laboratory for Molecular Medicine, Orphanet
hereditary glaucoma, primary closed-angle
Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

COL18A1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL18A1	NM_001379500.1 link	c.1072G>C	p.Gly358Arg	missense_variant	Exon 8 of 42	ENST00000651438.1	NP_001366429.1
COL18A1	NM_130444.3 link	c.2317G>C	p.Gly773Arg	missense_variant	Exon 7 of 41		NP_569711.2	P39060
COL18A1	NM_030582.4 link	c.1612G>C	p.Gly538Arg	missense_variant	Exon 7 of 41		NP_085059.2	P39060D3DSM5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
COL18A1	ENST00000651438.1 link	c.1072G>C	p.Gly358Arg	missense_variant	Exon 8 of 42		NM_001379500.1	ENSP00000498485.1	P39060-2
COL18A1	ENST00000355480.10 link	c.1612G>C	p.Gly538Arg	missense_variant	Exon 7 of 41	1		ENSP00000347665.5	P39060-1
COL18A1	ENST00000359759.8 link	c.2317G>C	p.Gly773Arg	missense_variant	Exon 7 of 41	5		ENSP00000352798.4	P39060-3

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152228

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000130

AC:

AN:

153386

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000403

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000168

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000429

AC:

AN:

1399342

Hom.:

Cov.:

AF XY:

0.00000290

AC XY:

AN XY:

690372

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31732

American (AMR)

AF:

0.0000279

AC:

AN:

35824

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25152

East Asian (EAS)

AF:

0.00

AC:

AN:

35968

South Asian (SAS)

AF:

0.00

AC:

AN:

79332

European-Finnish (FIN)

AF:

0.00

AC:

AN:

48098

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5678

European-Non Finnish (NFE)

AF:

0.00000278

AC:

AN:

1079538

Other (OTH)

AF:

0.0000345

AC:

AN:

58020

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<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:

0.0000131

AC:

AN:

152228

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74362

show subpopulations

African (AFR)

AF:

0.0000241

AC:

AN:

41464

American (AMR)

AF:

0.0000654

AC:

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5196

South Asian (SAS)

AF:

0.00

AC:

AN:

4838

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10630

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68018

Other (OTH)

AF:

0.00

AC:

AN:

2094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.0000508

Hom.:

Bravo

AF:

0.0000378

ExAC

AF:

0.00000943

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Nov 29, 2016

Athena Diagnostics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Uncertain:1

Oct 17, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 358 of the COL18A1 protein (p.Gly358Arg). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. 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: 447110). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.29

BayesDel_addAF

Benign

-0.025

BayesDel_noAF

Benign

-0.27

CADD

Benign

(source)

DANN

Benign

0.90

DEOGEN2

Uncertain

0.56

.;.;D

Eigen

Benign

0.088

Eigen_PC

Benign

-0.24

FATHMM_MKL

Benign

0.52

LIST_S2

Uncertain

0.91

D;D;D

M_CAP

Uncertain

0.14

MetaRNN

Uncertain

0.45

T;T;T

MetaSVM

Benign

-0.64

MutationAssessor

Benign

1.9

.;.;L

PhyloP100

2.5

PrimateAI

Uncertain

0.57

PROVEAN

Uncertain

-3.7

D;D;D

REVEL

Benign

0.21

Sift

Uncertain

0.0020

D;D;D

Sift4G

Uncertain

0.055

T;T;D

Polyphen

1.0

D;D;D

Vest4

0.27

MutPred

0.55

.;.;Gain of methylation at G773 (P = 0.026);

MVP

0.70

MPC

0.080

ClinPred

0.49

GERP RS

0.55

RBP_binding_hub_radar

0.92

RBP_regulation_power_radar

2.2

Varity_R

0.47

gMVP

0.79

Mutation Taster

=89/11

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over