rs7499

Positions:

chr21-45512414-G-A

Variant summary

Our verdict is Benign. Variant got -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:7

Conservation

PhyloP100: -2.08

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 made for transcript

Verdict is Benign. Variant got -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 id is 261884.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr21-45512414-G-A is described in Lovd as [Benign].

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/exons	MANE	UniProt
COL18A1	NM_001379500.1 linkuse as main transcript	c.*16G>A		3_prime_UTR_variant	42/42	ENST00000651438.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL18A1	ENST00000651438.1 linkuse as main transcript	c.*16G>A		3_prime_UTR_variant	42/42		NM_001379500.1		P39060-2

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

GnomAD3 exomes

AF:

0.419

AC:

100466

AN:

239992

Hom.:

21123

AF XY:

0.416

AC XY:

54543

AN XY:

131108

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 SAS exome

AF:

0.419

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

Gnomad4 AFR exome

AF:

0.448

Gnomad4 AMR exome

AF:

0.420

Gnomad4 ASJ exome

AF:

0.386

Gnomad4 EAS exome

AF:

0.601

Gnomad4 SAS exome

AF:

0.419

Gnomad4 FIN exome

AF:

0.402

Gnomad4 NFE exome

AF:

0.396

Gnomad4 OTH exome

AF:

0.414

GnomAD4 genome

AF:

0.416

AC:

63260

AN:

152068

Hom.:

13265

Cov.:

AF XY:

0.420

AC XY:

31179

AN XY:

74322

show subpopulations

Gnomad4 AFR

AF:

0.439

Gnomad4 AMR

AF:

0.403

Gnomad4 ASJ

AF:

0.379

Gnomad4 EAS

AF:

0.573

Gnomad4 SAS

AF:

0.427

Gnomad4 FIN

AF:

0.412

Gnomad4 NFE

AF:

0.394

Gnomad4 OTH

AF:

0.436

Alfa

AF:

0.402

Hom.:

16202

Bravo

AF:

0.417

Asia WGS

AF:

0.486

AC:

1689

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Knobloch syndrome

Benign:4

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	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. -
Benign, criteria provided, single submitter	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	May 31, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 22, 2021	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

- -

Glaucoma, primary closed-angle

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 22, 2021

- -

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Feb 23, 2021

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

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.88

CADD

Benign

0.17

DANN

Benign

0.80

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over