21-45504469-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_001379500.1(COL18A1):c.2781C>T(p.Pro927Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0253 in 1,607,824 control chromosomes in the GnomAD database, including 640 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. P927P) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.024 ( 53 hom., cov: 33)

Exomes 𝑓: 0.025 ( 587 hom. )

Consequence

COL18A1
NM_001379500.1 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: -4.14

Publications

12 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 links:

SLC19A1 (HGNC:10937): (solute carrier family 19 member 1) The membrane protein encoded by this gene is a transporter of folate and is involved in the regulation of intracellular concentrations of folate. Three transcript variants encoding different isoforms have been found for this gene.[provided by RefSeq, Mar 2011]

SLC19A1 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=-0.79).

BP6

Variant 21-45504469-C-T is Benign according to our data. Variant chr21-45504469-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 261906.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-4.14 with no splicing effect.

BS1

Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.0237 (3586/151046) while in subpopulation SAS AF = 0.0398 (190/4778). AF 95% confidence interval is 0.0351. There are 53 homozygotes in GnomAd4. There are 1832 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 53 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL18A1	NM_001379500.1 link	c.2781C>T	p.Pro927Pro	synonymous_variant	Exon 34 of 42	ENST00000651438.1	NP_001366429.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL18A1	ENST00000651438.1 link	c.2781C>T	p.Pro927Pro	synonymous_variant	Exon 34 of 42		NM_001379500.1	ENSP00000498485.1		P39060-2

Frequencies

GnomAD3 genomes

AF:

0.0237

AC:

3582

AN:

150928

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00837

Gnomad AMI

AF:

0.0419

Gnomad AMR

AF:

0.0328

Gnomad ASJ

AF:

0.0531

Gnomad EAS

AF:

0.0361

Gnomad SAS

AF:

0.0404

Gnomad FIN

AF:

0.0298

Gnomad MID

AF:

0.0348

Gnomad NFE

AF:

0.0259

Gnomad OTH

AF:

0.0328

GnomAD2 exomes

AF:

0.0291

AC:

6877

AN:

236534

AF XY:

0.0307

show subpopulations

Gnomad AFR exome

AF:

0.00922

Gnomad AMR exome

AF:

0.0249

Gnomad ASJ exome

AF:

0.0573

Gnomad EAS exome

AF:

0.0312

Gnomad FIN exome

AF:

0.0286

Gnomad NFE exome

AF:

0.0257

Gnomad OTH exome

AF:

0.0349

GnomAD4 exome

AF:

0.0255

AC:

37131

AN:

1456778

Hom.:

587

Cov.:

AF XY:

0.0264

AC XY:

19100

AN XY:

724694

show subpopulations

African (AFR)

AF:

0.00859

AC:

287

AN:

33398

American (AMR)

AF:

0.0266

AC:

1188

AN:

44636

Ashkenazi Jewish (ASJ)

AF:

0.0566

AC:

1476

AN:

26062

East Asian (EAS)

AF:

0.0307

AC:

1216

AN:

39662

South Asian (SAS)

AF:

0.0428

AC:

3684

AN:

86084

European-Finnish (FIN)

AF:

0.0263

AC:

1364

AN:

51810

Middle Eastern (MID)

AF:

0.0362

AC:

193

AN:

5330

European-Non Finnish (NFE)

AF:

0.0234

AC:

26018

AN:

1109718

Other (OTH)

AF:

0.0284

AC:

1705

AN:

60078

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.468

Heterozygous variant carriers

1701

3401

5102

6802

8503

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

980

1960

2940

3920

4900

<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:

0.0237

AC:

3586

AN:

151046

Hom.:

Cov.:

AF XY:

0.0248

AC XY:

1832

AN XY:

73806

show subpopulations

African (AFR)

AF:

0.00837

AC:

344

AN:

41100

American (AMR)

AF:

0.0327

AC:

496

AN:

15176

Ashkenazi Jewish (ASJ)

AF:

0.0531

AC:

184

AN:

3468

East Asian (EAS)

AF:

0.0364

AC:

183

AN:

5034

South Asian (SAS)

AF:

0.0398

AC:

190

AN:

4778

European-Finnish (FIN)

AF:

0.0298

AC:

313

AN:

10504

Middle Eastern (MID)

AF:

0.0377

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.0259

AC:

1753

AN:

67692

Other (OTH)

AF:

0.0353

AC:

AN:

2096

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.493

Heterozygous variant carriers

191

382

572

763

954

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

144

192

240

<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:

0.0227

Hom.:

Bravo

AF:

0.0227

Asia WGS

AF:

0.0300

AC:

103

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 04, 2021

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

See Variant Classification Assertion Criteria. -

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Knobloch syndrome

Benign:3

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. -

Jan 23, 2017

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Sep 21, 2015

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:1

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.79

CADD

Benign

0.13

(source)

DANN

Benign

0.81

PhyloP100

-4.1

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

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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