rs73370824

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_130444.3(COL18A1):c.3079-23C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0717 in 1,611,454 control chromosomes in the GnomAD database, including 5,666 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). There are indicators that this mutation may affect the branch point..

Frequency

Genomes: 𝑓 0.11 ( 1331 hom., cov: 33)

Exomes 𝑓: 0.068 ( 4335 hom. )

Consequence

COL18A1
NM_130444.3 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: -3.20

Publications

7 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 -20 ACMG points.

BP4

This position, referring to a specific DNA site, is a probable branch point but is likely benign (scored 1 / 10, using the threshold of <=3). The score ranges from 0 to 10, with values ≤3 considered benign and >5 classified as pathogenic. Computational evidence support a benign effect (BayesDel_noAF=-0.92).

BP6

Variant 21-45487424-C-A is Benign according to our data. Variant chr21-45487424-C-A is described in ClinVar as Benign. ClinVar VariationId is 261894.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.221 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_130444.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
COL18A1	NM_001379500.1	MANE Select	c.1834-23C>A	intron	N/A	NP_001366429.1
COL18A1	NM_130444.3		c.3079-23C>A	intron	N/A	NP_569711.2
COL18A1	NM_030582.4		c.2374-23C>A	intron	N/A	NP_085059.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
COL18A1	ENST00000651438.1	MANE Select	c.1834-23C>A	intron	N/A	ENSP00000498485.1
COL18A1	ENST00000355480.10	TSL:1	c.2374-23C>A	intron	N/A	ENSP00000347665.5
COL18A1	ENST00000359759.8	TSL:5	c.3079-23C>A	intron	N/A	ENSP00000352798.4

Frequencies

GnomAD3 genomes

AF:

0.107

AC:

16339

AN:

152124

Hom.:

1330

Cov.:

show subpopulations

Gnomad AFR

AF:

0.225

Gnomad AMI

AF:

0.0285

Gnomad AMR

AF:

0.0778

Gnomad ASJ

AF:

0.0516

Gnomad EAS

AF:

0.0998

Gnomad SAS

AF:

0.106

Gnomad FIN

AF:

0.0160

Gnomad MID

AF:

0.0696

Gnomad NFE

AF:

0.0617

Gnomad OTH

AF:

0.0942

GnomAD2 exomes

AF:

0.0730

AC:

18099

AN:

247794

AF XY:

0.0719

show subpopulations

Gnomad AFR exome

AF:

0.228

Gnomad AMR exome

AF:

0.0503

Gnomad ASJ exome

AF:

0.0480

Gnomad EAS exome

AF:

0.0959

Gnomad FIN exome

AF:

0.0199

Gnomad NFE exome

AF:

0.0607

Gnomad OTH exome

AF:

0.0669

GnomAD4 exome

AF:

0.0679

AC:

99141

AN:

1459212

Hom.:

4335

Cov.:

AF XY:

0.0682

AC XY:

49529

AN XY:

725924

show subpopulations

African (AFR)

AF:

0.235

AC:

7878

AN:

33460

American (AMR)

AF:

0.0549

AC:

2456

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.0477

AC:

1247

AN:

26130

East Asian (EAS)

AF:

0.139

AC:

5512

AN:

39692

South Asian (SAS)

AF:

0.0945

AC:

8150

AN:

86228

European-Finnish (FIN)

AF:

0.0202

AC:

1045

AN:

51810

Middle Eastern (MID)

AF:

0.0825

AC:

442

AN:

5360

European-Non Finnish (NFE)

AF:

0.0609

AC:

67659

AN:

1111502

Other (OTH)

AF:

0.0788

AC:

4752

AN:

60308

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.495

Heterozygous variant carriers

4651

9302

13953

18604

23255

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

2704

5408

8112

10816

13520

<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:

0.107

AC:

16351

AN:

152242

Hom.:

1331

Cov.:

AF XY:

0.104

AC XY:

7739

AN XY:

74442

show subpopulations

African (AFR)

AF:

0.225

AC:

9355

AN:

41526

American (AMR)

AF:

0.0775

AC:

1186

AN:

15312

Ashkenazi Jewish (ASJ)

AF:

0.0516

AC:

179

AN:

3472

East Asian (EAS)

AF:

0.0999

AC:

515

AN:

5156

South Asian (SAS)

AF:

0.105

AC:

508

AN:

4818

European-Finnish (FIN)

AF:

0.0160

AC:

170

AN:

10630

Middle Eastern (MID)

AF:

0.0612

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0617

AC:

4197

AN:

68008

Other (OTH)

AF:

0.0932

AC:

197

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

704

1409

2113

2818

3522

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

178

356

534

712

890

<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:

0.0329

Hom.:

Bravo

AF:

0.117

Asia WGS

AF:

0.110

AC:

382

AN:

3478

ClinVar

ClinVar submissions as Germline

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.92

CADD

Benign

0.063

(source)

DANN

Benign

0.62

PhyloP100

-3.2

BranchPoint Hunter

1.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Mutation Taster

=100/0

polymorphism (auto)

(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

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over