21-45512414-G-A

Variant names:

Variant summary

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

The NM_001379500.1(COL18A1):c.*16G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.407 in 1,608,724 control chromosomes in the GnomAD database, including 134,572 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.42 ( 13265 hom., cov: 33)

Exomes 𝑓: 0.41 ( 121307 hom. )

Consequence

COL18A1
NM_001379500.1 3_prime_UTR

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: -2.08

Publications

47 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 -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.88).

BP6

Variant 21-45512414-G-A is Benign according to our data. Variant chr21-45512414-G-A is described in ClinVar as Benign. ClinVar VariationId is 261884.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.555 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL18A1	NM_001379500.1 link	c.*16G>A		3_prime_UTR_variant	Exon 42 of 42	ENST00000651438.1	NP_001366429.1
SLC19A1	NM_194255.4 link	c.*3244C>T		downstream_gene_variant		ENST00000311124.9	NP_919231.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL18A1	ENST00000651438.1 link	c.*16G>A		3_prime_UTR_variant	Exon 42 of 42		NM_001379500.1	ENSP00000498485.1		P39060-2
SLC19A1	ENST00000311124.9 link	c.*3244C>T		downstream_gene_variant		1	NM_194255.4	ENSP00000308895.4		P41440-1

Frequencies

GnomAD3 genomes

AF:

0.416

AC:

63233

AN:

151950

Hom.:

13255

Cov.:

show subpopulations

Gnomad AFR

AF:

0.439

Gnomad AMI

AF:

0.388

Gnomad AMR

AF:

0.404

Gnomad ASJ

AF:

0.379

Gnomad EAS

AF:

0.572

Gnomad SAS

AF:

0.426

Gnomad FIN

AF:

0.412

Gnomad MID

AF:

0.449

Gnomad NFE

AF:

0.394

Gnomad OTH

AF:

0.438

GnomAD2 exomes

AF:

0.419

AC:

100466

AN:

239992

AF XY:

0.416

show subpopulations

Gnomad AFR exome

AF:

0.446

Gnomad AMR exome

AF:

0.420

Gnomad ASJ exome

AF:

0.383

Gnomad EAS exome

AF:

0.570

Gnomad FIN exome

AF:

0.404

Gnomad NFE exome

AF:

0.396

Gnomad OTH exome

AF:

0.429

GnomAD4 exome

AF:

0.406

AC:

590934

AN:

1456656

Hom.:

121307

Cov.:

AF XY:

0.405

AC XY:

293592

AN XY:

724348

show subpopulations

African (AFR)

AF:

0.448

AC:

14955

AN:

33414

American (AMR)

AF:

0.420

AC:

18572

AN:

44238

Ashkenazi Jewish (ASJ)

AF:

0.386

AC:

10048

AN:

26036

East Asian (EAS)

AF:

0.601

AC:

23774

AN:

39578

South Asian (SAS)

AF:

0.419

AC:

35898

AN:

85728

European-Finnish (FIN)

AF:

0.402

AC:

20796

AN:

51758

Middle Eastern (MID)

AF:

0.459

AC:

2606

AN:

5678

European-Non Finnish (NFE)

AF:

0.396

AC:

439368

AN:

1110016

Other (OTH)

AF:

0.414

AC:

24917

AN:

60210

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

Heterozygous variant carriers

19865

39730

59596

79461

99326

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

13810

27620

41430

55240

69050

<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:

0.416

AC:

63260

AN:

152068

Hom.:

13265

Cov.:

AF XY:

0.420

AC XY:

31179

AN XY:

74322

show subpopulations

African (AFR)

AF:

0.439

AC:

18213

AN:

41478

American (AMR)

AF:

0.403

AC:

6160

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.379

AC:

1315

AN:

3472

East Asian (EAS)

AF:

0.573

AC:

2955

AN:

5160

South Asian (SAS)

AF:

0.427

AC:

2058

AN:

4822

European-Finnish (FIN)

AF:

0.412

AC:

4358

AN:

10576

Middle Eastern (MID)

AF:

0.459

AC:

134

AN:

292

European-Non Finnish (NFE)

AF:

0.394

AC:

26791

AN:

67950

Other (OTH)

AF:

0.436

AC:

922

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.494

Heterozygous variant carriers

1921

3842

5764

7685

9606

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

600

1200

1800

2400

3000

<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:

0.405

Hom.:

30577

Bravo

AF:

0.417

Asia WGS

AF:

0.486

AC:

1689

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Knobloch syndrome

Benign:4

Jul 22, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

May 31, 2017

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

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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. -

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Feb 23, 2021

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 22461898, 21118967) -

not specified

Benign:1

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Hereditary glaucoma, primary closed-angle

Benign:1

Jul 22, 2021

Genome-Nilou Lab

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

-0.88

CADD

Benign

0.17

(source)

DANN

Benign

0.80

PhyloP100

-2.1

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

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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