Variant summary

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

The NM_130444.3(COL18A1):c.2091G>T(p.Thr697Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.121 in 1,613,426 control chromosomes in the GnomAD database, including 15,414 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. T697T) has been classified as Benign.

Frequency

Genomes: 𝑓 0.18 ( 3315 hom., cov: 33)

Exomes 𝑓: 0.12 ( 12099 hom. )

Consequence

COL18A1
NM_130444.3 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 0.148

Publications

24 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=-0.77).

BP6

Variant 21-45476398-G-T is Benign according to our data. Variant chr21-45476398-G-T is described in ClinVar as Benign. ClinVar VariationId is 261887.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=0.148 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.329 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	HGVSp	Effect	Exon Rank	Protein
COL18A1	NM_001379500.1	MANE Select	c.846G>T	p.Thr282Thr	synonymous	Exon 6 of 42	NP_001366429.1
COL18A1	NM_130444.3		c.2091G>T	p.Thr697Thr	synonymous	Exon 5 of 41	NP_569711.2
COL18A1	NM_030582.4		c.1386G>T	p.Thr462Thr	synonymous	Exon 5 of 41	NP_085059.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
COL18A1	ENST00000651438.1	MANE Select	c.846G>T	p.Thr282Thr	synonymous	Exon 6 of 42	ENSP00000498485.1
COL18A1	ENST00000355480.10	TSL:1	c.1386G>T	p.Thr462Thr	synonymous	Exon 5 of 41	ENSP00000347665.5
COL18A1	ENST00000359759.8	TSL:5	c.2091G>T	p.Thr697Thr	synonymous	Exon 5 of 41	ENSP00000352798.4

Frequencies

GnomAD3 genomes

AF:

0.179

AC:

27177

AN:

151934

Hom.:

3308

Cov.:

show subpopulations

Gnomad AFR

AF:

0.334

Gnomad AMI

AF:

0.151

Gnomad AMR

AF:

0.133

Gnomad ASJ

AF:

0.162

Gnomad EAS

AF:

0.300

Gnomad SAS

AF:

0.169

Gnomad FIN

AF:

0.120

Gnomad MID

AF:

0.161

Gnomad NFE

AF:

0.0976

Gnomad OTH

AF:

0.164

GnomAD2 exomes

AF:

0.142

AC:

35205

AN:

247142

AF XY:

0.140

show subpopulations

Gnomad AFR exome

AF:

0.333

Gnomad AMR exome

AF:

0.133

Gnomad ASJ exome

AF:

0.141

Gnomad EAS exome

AF:

0.300

Gnomad FIN exome

AF:

0.111

Gnomad NFE exome

AF:

0.0946

Gnomad OTH exome

AF:

0.136

GnomAD4 exome

AF:

0.115

AC:

168310

AN:

1461372

Hom.:

12099

Cov.:

AF XY:

0.116

AC XY:

84268

AN XY:

726968

show subpopulations

African (AFR)

AF:

0.349

AC:

11661

AN:

33460

American (AMR)

AF:

0.131

AC:

5843

AN:

44628

Ashkenazi Jewish (ASJ)

AF:

0.146

AC:

3812

AN:

26126

East Asian (EAS)

AF:

0.320

AC:

12700

AN:

39652

South Asian (SAS)

AF:

0.163

AC:

14068

AN:

86196

European-Finnish (FIN)

AF:

0.115

AC:

6112

AN:

53376

Middle Eastern (MID)

AF:

0.149

AC:

862

AN:

5766

European-Non Finnish (NFE)

AF:

0.0942

AC:

104732

AN:

1111800

Other (OTH)

AF:

0.141

AC:

8520

AN:

60368

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

7956

15912

23869

31825

39781

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

4186

8372

12558

16744

20930

<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:

0.179

AC:

27217

AN:

152054

Hom.:

3315

Cov.:

AF XY:

0.181

AC XY:

13453

AN XY:

74348

show subpopulations

African (AFR)

AF:

0.334

AC:

13821

AN:

41408

American (AMR)

AF:

0.133

AC:

2028

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.162

AC:

561

AN:

3466

East Asian (EAS)

AF:

0.301

AC:

1551

AN:

5160

South Asian (SAS)

AF:

0.170

AC:

817

AN:

4818

European-Finnish (FIN)

AF:

0.120

AC:

1277

AN:

10600

Middle Eastern (MID)

AF:

0.163

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0976

AC:

6634

AN:

68004

Other (OTH)

AF:

0.163

AC:

343

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

1085

2170

3255

4340

5425

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

286

572

858

1144

1430

<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:

0.114

Hom.:

2373

Bravo

AF:

0.186

EpiCase

AF:

0.0973

EpiControl

AF:

0.0955

ClinVar

ClinVar submissions as Germline

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

Knobloch syndrome (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.77

CADD

Benign

0.74

(source)

DANN

Benign

0.38

PhyloP100

0.15

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

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

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over