rs144147445

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_StrongBS1BS2

The NM_001379500.1(COL18A1):c.3610G>A(p.Ala1204Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0158 in 1,597,036 control chromosomes in the GnomAD database, including 248 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.010 ( 18 hom., cov: 34)

Exomes 𝑓: 0.016 ( 230 hom. )

Consequence

COL18A1
NM_001379500.1 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 9.68

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 -16 ACMG points.

BP6

Variant 21-45510178-G-A is Benign according to our data. Variant chr21-45510178-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 261914.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr21-45510178-G-A is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.0101 (1539/152288) while in subpopulation SAS AF= 0.0209 (101/4826). AF 95% confidence interval is 0.0176. There are 18 homozygotes in gnomad4. There are 701 alleles in male gnomad4 subpopulation. Median coverage is 34. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 18 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL18A1	NM_001379500.1 link	c.3610G>A	p.Ala1204Thr	missense_variant	Exon 40 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.3610G>A	p.Ala1204Thr	missense_variant	Exon 40 of 42		NM_001379500.1	ENSP00000498485.1		P39060-2

Frequencies

GnomAD3 genomes

AF:

0.0101

AC:

1541

AN:

152170

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00319

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00386

Gnomad ASJ

AF:

0.0202

Gnomad EAS

AF:

0.000385

Gnomad SAS

AF:

0.0211

Gnomad FIN

AF:

0.00782

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.0157

Gnomad OTH

AF:

0.0105

GnomAD3 exomes

AF:

0.0127

AC:

2670

AN:

209828

Hom.:

AF XY:

0.0143

AC XY:

1662

AN XY:

115988

show subpopulations

Gnomad AFR exome

AF:

0.00290

Gnomad AMR exome

AF:

0.00485

Gnomad ASJ exome

AF:

0.0184

Gnomad EAS exome

AF:

0.000254

Gnomad SAS exome

AF:

0.0234

Gnomad FIN exome

AF:

0.00604

Gnomad NFE exome

AF:

0.0164

Gnomad OTH exome

AF:

0.0127

GnomAD4 exome

AF:

0.0164

AC:

23693

AN:

1444748

Hom.:

230

Cov.:

AF XY:

0.0167

AC XY:

12018

AN XY:

717598

show subpopulations

Gnomad4 AFR exome

AF:

0.00276

Gnomad4 AMR exome

AF:

0.00525

Gnomad4 ASJ exome

AF:

0.0194

Gnomad4 EAS exome

AF:

0.000235

Gnomad4 SAS exome

AF:

0.0228

Gnomad4 FIN exome

AF:

0.00629

Gnomad4 NFE exome

AF:

0.0177

Gnomad4 OTH exome

AF:

0.0152

GnomAD4 genome

AF:

0.0101

AC:

1539

AN:

152288

Hom.:

Cov.:

AF XY:

0.00941

AC XY:

701

AN XY:

74462

show subpopulations

Gnomad4 AFR

AF:

0.00318

Gnomad4 AMR

AF:

0.00386

Gnomad4 ASJ

AF:

0.0202

Gnomad4 EAS

AF:

0.000386

Gnomad4 SAS

AF:

0.0209

Gnomad4 FIN

AF:

0.00782

Gnomad4 NFE

AF:

0.0157

Gnomad4 OTH

AF:

0.0104

Alfa

AF:

0.0162

Hom.:

Bravo

AF:

0.00926

TwinsUK

AF:

0.0146

AC:

ALSPAC

AF:

0.0166

AC:

ESP6500AA

AF:

0.00330

AC:

ESP6500EA

AF:

0.0144

AC:

118

ExAC

AF:

0.0123

AC:

1463

Asia WGS

AF:

0.00635

AC:

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:5

Jan 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

COL18A1: BS1, BS2; SLC19A1: BS1, BS2 -

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not specified

Benign:2

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 27, 2018

Genetic Services Laboratory, University of Chicago

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.89

BayesDel_addAF

Benign

-0.12

BayesDel_noAF

Uncertain

0.080

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.43

.;.;T;T

Eigen

Pathogenic

0.79

Eigen_PC

Pathogenic

0.67

FATHMM_MKL

Uncertain

0.96

LIST_S2

Pathogenic

0.99

D;D;D;D

MetaRNN

Benign

0.018

T;T;T;T

MetaSVM

Uncertain

0.090

MutationAssessor

Pathogenic

3.8

.;.;H;.

PrimateAI

Uncertain

0.76

PROVEAN

Uncertain

-3.4

D;D;D;D

REVEL

Uncertain

0.51

Sift

Pathogenic

0.0

D;T;D;D

Sift4G

Pathogenic

0.0

D;D;D;D

Polyphen

1.0

D;D;D;.

Vest4

0.68

MPC

0.40

ClinPred

0.065

GERP RS

4.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.8

Varity_R

0.69

gMVP

0.90

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.24

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.24

Position offset: 24

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