rs76547444

Variant names:

Variant summary

Our verdict is Benign. The variant received -15 ACMG points: 1P and 16B. PP3BP6_Very_StrongBS1BS2

The NM_001379500.1(COL18A1):c.1009G>A(p.Gly337Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00204 in 1,537,764 control chromosomes in the GnomAD database, including 59 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/23 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.011 ( 32 hom., cov: 33)

Exomes 𝑓: 0.0011 ( 27 hom. )

Consequence

COL18A1
NM_001379500.1 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 3.02

Publications

4 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: Benign. The variant received -15 ACMG points.

PP3

Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

BP6

Variant 21-45477753-G-A is Benign according to our data. Variant chr21-45477753-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 340210.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 = 0.0105 (1601/152326) while in subpopulation AFR AF = 0.0356 (1480/41570). AF 95% confidence interval is 0.0341. There are 32 homozygotes in GnomAd4. There are 778 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 32 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
COL18A1	NM_001379500.1 link	c.1009G>A	p.Gly337Ser	missense_variant	Exon 8 of 42	ENST00000651438.1	NP_001366429.1
COL18A1	NM_130444.3 link	c.2254G>A	p.Gly752Ser	missense_variant	Exon 7 of 41		NP_569711.2
COL18A1	NM_030582.4 link	c.1549G>A	p.Gly517Ser	missense_variant	Exon 7 of 41		NP_085059.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
COL18A1	ENST00000651438.1 link	c.1009G>A	p.Gly337Ser	missense_variant	Exon 8 of 42		NM_001379500.1	ENSP00000498485.1
COL18A1	ENST00000355480.10 link	c.1549G>A	p.Gly517Ser	missense_variant	Exon 7 of 41	1		ENSP00000347665.5
COL18A1	ENST00000359759.8 link	c.2254G>A	p.Gly752Ser	missense_variant	Exon 7 of 41	5		ENSP00000352798.4

Frequencies

GnomAD3 genomes

AF:

0.0105

AC:

1597

AN:

152208

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0356

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00595

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000413

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000103

Gnomad OTH

AF:

0.00956

GnomAD2 exomes

AF:

0.00222

AC:

315

AN:

141732

AF XY:

0.00181

show subpopulations

Gnomad AFR exome

AF:

0.0354

Gnomad AMR exome

AF:

0.00198

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000917

Gnomad OTH exome

AF:

0.00217

GnomAD4 exome

AF:

0.00110

AC:

1529

AN:

1385438

Hom.:

Cov.:

AF XY:

0.000942

AC XY:

643

AN XY:

682414

show subpopulations

African (AFR)

AF:

0.0388

AC:

1217

AN:

31394

American (AMR)

AF:

0.00261

AC:

AN:

35306

Ashkenazi Jewish (ASJ)

AF:

0.0000403

AC:

AN:

24844

East Asian (EAS)

AF:

0.00

AC:

AN:

35566

South Asian (SAS)

AF:

0.000127

AC:

AN:

78938

European-Finnish (FIN)

AF:

0.00

AC:

AN:

42410

Middle Eastern (MID)

AF:

0.00197

AC:

AN:

5576

European-Non Finnish (NFE)

AF:

0.0000428

AC:

AN:

1073898

Other (OTH)

AF:

0.00264

AC:

152

AN:

57506

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.472

Heterozygous variant carriers

150

226

301

376

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

126

168

210

<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:

0.0105

AC:

1601

AN:

152326

Hom.:

Cov.:

AF XY:

0.0104

AC XY:

778

AN XY:

74476

show subpopulations

African (AFR)

AF:

0.0356

AC:

1480

AN:

41570

American (AMR)

AF:

0.00595

AC:

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.000288

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5180

South Asian (SAS)

AF:

0.000414

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10628

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000103

AC:

AN:

68016

Other (OTH)

AF:

0.00946

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

155

232

310

387

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:

0.00227

Hom.:

Bravo

AF:

0.0122

ESP6500AA

AF:

0.0290

AC:

ESP6500EA

AF:

0.000268

AC:

ExAC

AF:

0.00147

AC:

125

Asia WGS

AF:

0.00202

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

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 30, 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

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Knobloch syndrome

Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.082

BayesDel_addAF

Benign

-0.46

BayesDel_noAF

Benign

-0.40

CADD

Uncertain

(source)

DANN

Benign

0.96

DEOGEN2

Benign

0.12

.;.;T

Eigen

Benign

-0.21

Eigen_PC

Benign

-0.35

FATHMM_MKL

Benign

0.066

LIST_S2

Benign

0.61

T;T;T

MetaRNN

Benign

0.0034

T;T;T

MetaSVM

Benign

-0.82

MutationAssessor

Benign

1.9

.;.;L

PhyloP100

3.0

PrimateAI

Benign

0.39

PROVEAN

Uncertain

-3.0

D;D;D

REVEL

Benign

0.18

Sift

Uncertain

0.021

D;D;D

Sift4G

Benign

0.14

T;T;T

Polyphen

0.58

P;P;P

Vest4

0.087

MVP

0.59

MPC

0.067

ClinPred

0.021

GERP RS

3.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.11

gMVP

0.74

Mutation Taster

=97/3

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.61

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.61

Position offset: 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