rs12483377

Positions:

chr21-45511195-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.3778G>A(p.Asp1260Asn) variant causes a missense change. The variant allele was found at a frequency of 0.0783 in 1,592,926 control chromosomes in the GnomAD database, including 5,341 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. D1260D) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.066 ( 370 hom., cov: 31)

Exomes 𝑓: 0.080 ( 4971 hom. )

Consequence

COL18A1
NM_001379500.1 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts P:1B:9

Conservation

PhyloP100: 6.54

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 (MetaRNN=0.005586356).

BP6

Variant 21-45511195-G-A is Benign according to our data. Variant chr21-45511195-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 17118.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr21-45511195-G-A is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0887 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COL18A1	NM_001379500.1 link	c.3778G>A	p.Asp1260Asn	missense_variant	41/42	ENST00000651438.1	NP_001366429.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COL18A1	ENST00000651438.1 link	c.3778G>A	p.Asp1260Asn	missense_variant	41/42		NM_001379500.1	ENSP00000498485.1		P39060-2

Frequencies

GnomAD3 genomes

AF:

0.0662

AC:

10055

AN:

151896

Hom.:

370

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0365

Gnomad AMI

AF:

0.0604

Gnomad AMR

AF:

0.0629

Gnomad ASJ

AF:

0.102

Gnomad EAS

AF:

0.0159

Gnomad SAS

AF:

0.0462

Gnomad FIN

AF:

0.0515

Gnomad MID

AF:

0.0728

Gnomad NFE

AF:

0.0906

Gnomad OTH

AF:

0.0714

GnomAD3 exomes

AF:

0.0656

AC:

14042

AN:

214196

Hom.:

537

AF XY:

0.0666

AC XY:

7722

AN XY:

115908

show subpopulations

Gnomad AFR exome

AF:

0.0359

Gnomad AMR exome

AF:

0.0403

Gnomad ASJ exome

AF:

0.103

Gnomad EAS exome

AF:

0.0155

Gnomad SAS exome

AF:

0.0476

Gnomad FIN exome

AF:

0.0565

Gnomad NFE exome

AF:

0.0886

Gnomad OTH exome

AF:

0.0769

GnomAD4 exome

AF:

0.0796

AC:

114648

AN:

1440912

Hom.:

4971

Cov.:

AF XY:

0.0791

AC XY:

56558

AN XY:

715102

show subpopulations

Gnomad4 AFR exome

AF:

0.0336

Gnomad4 AMR exome

AF:

0.0431

Gnomad4 ASJ exome

AF:

0.101

Gnomad4 EAS exome

AF:

0.0104

Gnomad4 SAS exome

AF:

0.0496

Gnomad4 FIN exome

AF:

0.0540

Gnomad4 NFE exome

AF:

0.0880

Gnomad4 OTH exome

AF:

0.0757

GnomAD4 genome

AF:

0.0661

AC:

10054

AN:

152014

Hom.:

370

Cov.:

AF XY:

0.0635

AC XY:

4718

AN XY:

74300

show subpopulations

Gnomad4 AFR

AF:

0.0364

Gnomad4 AMR

AF:

0.0628

Gnomad4 ASJ

AF:

0.102

Gnomad4 EAS

AF:

0.0157

Gnomad4 SAS

AF:

0.0458

Gnomad4 FIN

AF:

0.0515

Gnomad4 NFE

AF:

0.0906

Gnomad4 OTH

AF:

0.0706

Alfa

AF:

0.0850

Hom.:

1302

Bravo

AF:

0.0650

TwinsUK

AF:

0.0968

AC:

359

ALSPAC

AF:

0.0939

AC:

362

ESP6500AA

AF:

0.0358

AC:

142

ESP6500EA

AF:

0.0878

AC:

732

ExAC

AF:

0.0586

AC:

7022

Asia WGS

AF:

0.0310

AC:

110

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Pathogenic:1Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 23, 2021	This variant is associated with the following publications: (PMID: 11606364, 15714516, 16115201, 14695535, 15662127, 16807676, 26542764) -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	May 07, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

Knobloch syndrome

Pathogenic:1Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	Sep 21, 2015	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jan 01, 2004	- -

not specified

Benign:3

Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.46

BayesDel_noAF

Benign

-0.36

CADD

Uncertain

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.21

.;.;T;T

Eigen

Uncertain

0.55

Eigen_PC

Uncertain

0.49

FATHMM_MKL

Uncertain

0.85

LIST_S2

Uncertain

0.94

D;D;D;D

MetaRNN

Benign

0.0056

T;T;T;T

MetaSVM

Benign

-0.94

MutationAssessor

Uncertain

2.4

.;.;M;.

PrimateAI

Uncertain

0.69

PROVEAN

Uncertain

-3.9

D;D;D;D

REVEL

Uncertain

0.42

Sift

Benign

0.057

T;T;T;T

Sift4G

Pathogenic

0.0

D;D;D;T

Polyphen

1.0

D;D;D;.

Vest4

0.49

MPC

0.38

ClinPred

0.0098

GERP RS

5.0

Varity_R

0.59

gMVP

0.67

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