Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_001379500.1(COL18A1):c.1143G>A(p.Ala381Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00835 in 1,562,254 control chromosomes in the GnomAD database, including 275 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. A381A) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0069 ( 30 hom., cov: 33)

Exomes 𝑓: 0.0085 ( 245 hom. )

Consequence

COL18A1
NM_001379500.1 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: -0.773

Publications

6 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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.81).

BP6

Variant 21-45477887-G-A is Benign according to our data. Variant chr21-45477887-G-A is described in ClinVar as Benign. ClinVar VariationId is 261889.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.773 with no splicing effect.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0698 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001379500.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
COL18A1	NM_001379500.1	MANE Select	c.1143G>A	p.Ala381Ala	synonymous	Exon 8 of 42	NP_001366429.1
COL18A1	NM_130444.3		c.2388G>A	p.Ala796Ala	synonymous	Exon 7 of 41	NP_569711.2
COL18A1	NM_030582.4		c.1683G>A	p.Ala561Ala	synonymous	Exon 7 of 41	NP_085059.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
COL18A1	ENST00000651438.1	MANE Select	c.1143G>A	p.Ala381Ala	synonymous	Exon 8 of 42	ENSP00000498485.1
COL18A1	ENST00000355480.10	TSL:1	c.1683G>A	p.Ala561Ala	synonymous	Exon 7 of 41	ENSP00000347665.5
COL18A1	ENST00000359759.8	TSL:5	c.2388G>A	p.Ala796Ala	synonymous	Exon 7 of 41	ENSP00000352798.4

Frequencies

GnomAD3 genomes

AF:

0.00690

AC:

1050

AN:

152208

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00166

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00373

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.0763

Gnomad SAS

AF:

0.0449

Gnomad FIN

AF:

0.00132

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00426

Gnomad OTH

AF:

0.00335

GnomAD2 exomes

AF:

0.0142

AC:

2402

AN:

169700

AF XY:

0.0154

show subpopulations

Gnomad AFR exome

AF:

0.000789

Gnomad AMR exome

AF:

0.00157

Gnomad ASJ exome

AF:

0.00161

Gnomad EAS exome

AF:

0.0861

Gnomad FIN exome

AF:

0.00155

Gnomad NFE exome

AF:

0.00420

Gnomad OTH exome

AF:

0.00648

GnomAD4 exome

AF:

0.00851

AC:

11995

AN:

1409928

Hom.:

245

Cov.:

AF XY:

0.00922

AC XY:

6427

AN XY:

696882

show subpopulations

African (AFR)

AF:

0.000936

AC:

AN:

32062

American (AMR)

AF:

0.00154

AC:

AN:

37576

Ashkenazi Jewish (ASJ)

AF:

0.00178

AC:

AN:

25296

East Asian (EAS)

AF:

0.0877

AC:

3202

AN:

36524

South Asian (SAS)

AF:

0.0383

AC:

3062

AN:

80044

European-Finnish (FIN)

AF:

0.00120

AC:

AN:

49070

Middle Eastern (MID)

AF:

0.00210

AC:

AN:

5714

European-Non Finnish (NFE)

AF:

0.00457

AC:

4957

AN:

1085276

Other (OTH)

AF:

0.00977

AC:

570

AN:

58366

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.471

Heterozygous variant carriers

595

1190

1784

2379

2974

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

268

536

804

1072

1340

<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:

0.00687

AC:

1046

AN:

152326

Hom.:

Cov.:

AF XY:

0.00777

AC XY:

579

AN XY:

74480

show subpopulations

African (AFR)

AF:

0.00166

AC:

AN:

41578

American (AMR)

AF:

0.00372

AC:

AN:

15314

Ashkenazi Jewish (ASJ)

AF:

0.000288

AC:

AN:

3472

East Asian (EAS)

AF:

0.0760

AC:

393

AN:

5168

South Asian (SAS)

AF:

0.0445

AC:

215

AN:

4834

European-Finnish (FIN)

AF:

0.00132

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00426

AC:

290

AN:

68016

Other (OTH)

AF:

0.00331

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

145

193

241

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:

0.00434

Hom.:

Bravo

AF:

0.00603

Asia WGS

AF:

0.0480

AC:

166

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 (3)

not specified (2)

Knobloch syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.81

CADD

Benign

5.8

(source)

DANN

Benign

0.45

PhyloP100

-0.77

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)

0.010

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over