rs61736805

Positions:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001379500.1(COL18A1):c.3823G>T(p.Val1275Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00409 in 1,612,314 control chromosomes in the GnomAD database, including 114 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.013 ( 32 hom., cov: 33)

Exomes 𝑓: 0.0032 ( 82 hom. )

Consequence

COL18A1
NM_001379500.1 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 2.14

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=0.011089116).

BP6

Variant 21-45512201-G-T is Benign according to our data. Variant chr21-45512201-G-T is described in ClinVar as [Likely_benign]. Clinvar id is 445580.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr21-45512201-G-T is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0126 (1922/152342) while in subpopulation AFR AF= 0.0402 (1672/41576). AF 95% confidence interval is 0.0386. There are 32 homozygotes in gnomad4. There are 922 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 32 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COL18A1	NM_001379500.1 linkuse as main transcript	c.3823G>T	p.Val1275Leu	missense_variant	42/42	ENST00000651438.1	NP_001366429.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COL18A1	ENST00000651438.1 linkuse as main transcript	c.3823G>T	p.Val1275Leu	missense_variant	42/42		NM_001379500.1	ENSP00000498485		P39060-2

Frequencies

GnomAD3 genomes

AF:

0.0125

AC:

1906

AN:

152224

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0399

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00432

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00519

Gnomad SAS

AF:

0.0203

Gnomad FIN

AF:

0.000282

Gnomad MID

AF:

0.0158

Gnomad NFE

AF:

0.000559

Gnomad OTH

AF:

0.00621

GnomAD3 exomes

AF:

0.00649

AC:

1574

AN:

242486

Hom.:

AF XY:

0.00669

AC XY:

888

AN XY:

132664

show subpopulations

Gnomad AFR exome

AF:

0.0405

Gnomad AMR exome

AF:

0.00230

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00696

Gnomad SAS exome

AF:

0.0223

Gnomad FIN exome

AF:

0.000144

Gnomad NFE exome

AF:

0.000608

Gnomad OTH exome

AF:

0.00372

GnomAD4 exome

AF:

0.00320

AC:

4678

AN:

1459972

Hom.:

Cov.:

AF XY:

0.00362

AC XY:

2628

AN XY:

726296

show subpopulations

Gnomad4 AFR exome

AF:

0.0459

Gnomad4 AMR exome

AF:

0.00249

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00260

Gnomad4 SAS exome

AF:

0.0207

Gnomad4 FIN exome

AF:

0.000248

Gnomad4 NFE exome

AF:

0.000666

Gnomad4 OTH exome

AF:

0.00595

GnomAD4 genome

AF:

0.0126

AC:

1922

AN:

152342

Hom.:

Cov.:

AF XY:

0.0124

AC XY:

922

AN XY:

74504

show subpopulations

Gnomad4 AFR

AF:

0.0402

Gnomad4 AMR

AF:

0.00431

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00540

Gnomad4 SAS

AF:

0.0201

Gnomad4 FIN

AF:

0.000282

Gnomad4 NFE

AF:

0.000559

Gnomad4 OTH

AF:

0.00614

Alfa

AF:

0.00241

Hom.:

Bravo

AF:

0.0140

TwinsUK

AF:

0.000809

AC:

ALSPAC

AF:

0.000778

AC:

ESP6500AA

AF:

0.0363

AC:

150

ESP6500EA

AF:

0.000954

AC:

ExAC

AF:

0.00748

AC:

902

EpiCase

AF:

0.000654

EpiControl

AF:

0.000891

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:5

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Feb 23, 2017	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.17

BayesDel_addAF

Benign

-0.38

BayesDel_noAF

Benign

-0.28

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.14

.;.;T;T

Eigen

Benign

-0.14

Eigen_PC

Benign

-0.084

FATHMM_MKL

Uncertain

0.78

LIST_S2

Benign

0.85

T;T;T;T

MetaRNN

Benign

0.011

T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Uncertain

2.4

.;.;M;.

MutationTaster

Benign

1.0

D;D;D;D

PrimateAI

Uncertain

0.62

PROVEAN

Benign

-2.3

N;N;N;N

REVEL

Benign

0.18

Sift

Uncertain

0.010

D;T;D;D

Sift4G

Benign

0.23

T;T;T;T

Polyphen

0.037

B;B;B;.

Vest4

0.13

MutPred

0.70

.;.;Loss of sheet (P = 0.0817);.;

MVP

0.43

MPC

0.31

ClinPred

0.016

GERP RS

3.2

Varity_R

0.50

gMVP

0.64

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