21-45509458-G-A

Variant names:

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2

The NM_001379500.1(COL18A1):c.3352G>A(p.Ala1118Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0105 in 1,533,408 control chromosomes in the GnomAD database, including 120 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. A1118A) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0069 ( 6 hom., cov: 33)

Exomes 𝑓: 0.011 ( 114 hom. )

Consequence

COL18A1
NM_001379500.1 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 0.715

Publications

5 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 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 was made for transcript

Our verdict: Benign. The variant received -16 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0067158937).

BP6

Variant 21-45509458-G-A is Benign according to our data. Variant chr21-45509458-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 377047.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High Homozygotes in GnomAd4 at 6 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL18A1	NM_001379500.1 link	c.3352G>A	p.Ala1118Thr	missense_variant	Exon 39 of 42	ENST00000651438.1	NP_001366429.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL18A1	ENST00000651438.1 link	c.3352G>A	p.Ala1118Thr	missense_variant	Exon 39 of 42		NM_001379500.1	ENSP00000498485.1		P39060-2

Frequencies

GnomAD3 genomes

AF:

0.00687

AC:

1044

AN:

152058

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00181

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00321

Gnomad ASJ

AF:

0.00115

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00104

Gnomad FIN

AF:

0.00452

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0126

Gnomad OTH

AF:

0.00287

GnomAD2 exomes

AF:

0.00659

AC:

902

AN:

136796

AF XY:

0.00692

show subpopulations

Gnomad AFR exome

AF:

0.00302

Gnomad AMR exome

AF:

0.00275

Gnomad ASJ exome

AF:

0.00137

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00523

Gnomad NFE exome

AF:

0.0137

Gnomad OTH exome

AF:

0.00539

GnomAD4 exome

AF:

0.0110

AC:

15131

AN:

1381234

Hom.:

114

Cov.:

AF XY:

0.0107

AC XY:

7303

AN XY:

681828

show subpopulations

African (AFR)

AF:

0.00162

AC:

AN:

31548

American (AMR)

AF:

0.00284

AC:

103

AN:

36310

Ashkenazi Jewish (ASJ)

AF:

0.00120

AC:

AN:

25016

East Asian (EAS)

AF:

0.00

AC:

AN:

35870

South Asian (SAS)

AF:

0.00130

AC:

103

AN:

79244

European-Finnish (FIN)

AF:

0.00472

AC:

176

AN:

37288

Middle Eastern (MID)

AF:

0.00206

AC:

AN:

4856

European-Non Finnish (NFE)

AF:

0.0133

AC:

14314

AN:

1073608

Other (OTH)

AF:

0.00598

AC:

344

AN:

57494

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.480

Heterozygous variant carriers

712

1423

2135

2846

3558

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

536

1072

1608

2144

2680

<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:

0.00686

AC:

1044

AN:

152174

Hom.:

Cov.:

AF XY:

0.00629

AC XY:

468

AN XY:

74392

show subpopulations

African (AFR)

AF:

0.00181

AC:

AN:

41520

American (AMR)

AF:

0.00320

AC:

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.00115

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5176

South Asian (SAS)

AF:

0.00104

AC:

AN:

4818

European-Finnish (FIN)

AF:

0.00452

AC:

AN:

10612

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0126

AC:

857

AN:

67966

Other (OTH)

AF:

0.00284

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.487

Heterozygous variant carriers

104

155

207

259

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.00834

Hom.:

Bravo

AF:

0.00676

ESP6500AA

AF:

0.000634

AC:

ESP6500EA

AF:

0.00793

AC:

ExAC

AF:

0.00439

AC:

467

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Dec 01, 2016

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Apr 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

COL18A1: BS1, BS2 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.15

BayesDel_addAF

Benign

-0.30

BayesDel_noAF

Benign

-0.20

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.080

.;.;T;T

Eigen

Benign

-0.36

Eigen_PC

Benign

-0.37

FATHMM_MKL

Benign

0.098

LIST_S2

Benign

0.80

T;T;T;T

MetaRNN

Benign

0.0067

T;T;T;T

MetaSVM

Uncertain

-0.24

MutationAssessor

Benign

1.7

.;.;L;.

PhyloP100

0.71

PrimateAI

Uncertain

0.55

PROVEAN

Benign

-1.4

N;N;N;N

REVEL

Benign

0.28

Sift

Uncertain

0.011

D;D;D;T

Sift4G

Benign

0.10

T;T;T;T

Polyphen

0.57

P;P;P;.

Vest4

0.31

MVP

0.81

MPC

0.23

ClinPred

0.016

GERP RS

2.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.9

Varity_R

0.092

gMVP

0.47

Mutation Taster

=93/7

polymorphism

(source)

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

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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