chr21-45482789-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.1675-6G>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0025 in 1,614,160 control chromosomes in the GnomAD database, including 18 homozygotes. In-silico tool predicts a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0027 ( 6 hom., cov: 33)

Exomes 𝑓: 0.0025 ( 12 hom. )

Consequence

COL18A1
NM_001379500.1 splice_region, intron

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: 0.583

Publications

0 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 -16 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.86).

BP6

Variant 21-45482789-G-A is Benign according to our data. Variant chr21-45482789-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 261893.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	Effect	Exon rank	MANE	Protein	UniProt
COL18A1	NM_001379500.1 link	c.1675-6G>A	splice_region_variant, intron_variant	Intron 14 of 41	ENST00000651438.1	NP_001366429.1
COL18A1	NM_130444.3 link	c.2920-6G>A	splice_region_variant, intron_variant	Intron 13 of 40		NP_569711.2	P39060
COL18A1	NM_030582.4 link	c.2215-6G>A	splice_region_variant, intron_variant	Intron 13 of 40		NP_085059.2	P39060D3DSM5

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein	UniProt
COL18A1	ENST00000651438.1 link	c.1675-6G>A	splice_region_variant, intron_variant	Intron 14 of 41		NM_001379500.1	ENSP00000498485.1	P39060-2
COL18A1	ENST00000355480.10 link	c.2215-6G>A	splice_region_variant, intron_variant	Intron 13 of 40	1		ENSP00000347665.5	P39060-1
COL18A1	ENST00000359759.8 link	c.2920-6G>A	splice_region_variant, intron_variant	Intron 13 of 40	5		ENSP00000352798.4	P39060-3

Frequencies

GnomAD3 genomes

AF:

0.00271

AC:

412

AN:

152160

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000435

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00851

Gnomad ASJ

AF:

0.00979

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00228

Gnomad FIN

AF:

0.000565

Gnomad MID

AF:

0.0253

Gnomad NFE

AF:

0.00294

Gnomad OTH

AF:

0.00239

GnomAD2 exomes

AF:

0.00311

AC:

777

AN:

249542

AF XY:

0.00321

show subpopulations

Gnomad AFR exome

AF:

0.000517

Gnomad AMR exome

AF:

0.00501

Gnomad ASJ exome

AF:

0.0127

Gnomad EAS exome

AF:

0.0000556

Gnomad FIN exome

AF:

0.000557

Gnomad NFE exome

AF:

0.00343

Gnomad OTH exome

AF:

0.00478

GnomAD4 exome

AF:

0.00247

AC:

3618

AN:

1461882

Hom.:

Cov.:

AF XY:

0.00260

AC XY:

1892

AN XY:

727244

show subpopulations

African (AFR)

AF:

0.000627

AC:

AN:

33480

American (AMR)

AF:

0.00456

AC:

204

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0120

AC:

314

AN:

26136

East Asian (EAS)

AF:

0.0000756

AC:

AN:

39700

South Asian (SAS)

AF:

0.00139

AC:

120

AN:

86258

European-Finnish (FIN)

AF:

0.000674

AC:

AN:

53418

Middle Eastern (MID)

AF:

0.0109

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00239

AC:

2659

AN:

1112002

Other (OTH)

AF:

0.00328

AC:

198

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.458

Heterozygous variant carriers

213

426

638

851

1064

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

188

282

376

470

<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:

0.00271

AC:

412

AN:

152278

Hom.:

Cov.:

AF XY:

0.00285

AC XY:

212

AN XY:

74460

show subpopulations

African (AFR)

AF:

0.000433

AC:

AN:

41538

American (AMR)

AF:

0.00850

AC:

130

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.00979

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5174

South Asian (SAS)

AF:

0.00228

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.000565

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.0272

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00294

AC:

200

AN:

68032

Other (OTH)

AF:

0.00237

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.492

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

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:

0.00315

Hom.:

Bravo

AF:

0.00290

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.00540

EpiControl

AF:

0.00421

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Aug 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

COL18A1: BP4, BS2 -

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not specified

Benign:2

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Clinical Genetics, Academic Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Inborn genetic diseases

Benign:1

Jan 21, 2022

Ambry Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Knobloch syndrome

Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Likely 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.86

CADD

Benign

2.0

(source)

DANN

Benign

0.44

PhyloP100

0.58

Mutation Taster

=99/1

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

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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