21-45488441-T-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_001379500.1(COL18A1):c.1920T>C(p.Leu640=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.306 in 1,613,522 control chromosomes in the GnomAD database, including 76,375 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. L640L) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.32 ( 7874 hom., cov: 32)

Exomes 𝑓: 0.30 ( 68501 hom. )

Consequence

COL18A1
NM_001379500.1 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: -0.0120

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:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.83).

BP6

Variant 21-45488441-T-C is Benign according to our data. Variant chr21-45488441-T-C is described in ClinVar as [Benign]. Clinvar id is 261895.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr21-45488441-T-C is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=-0.012 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.361 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
COL18A1	NM_001379500.1 linkuse as main transcript	c.1920T>C	p.Leu640=	synonymous_variant	18/42	ENST00000651438.1
COL18A1	NM_130444.3 linkuse as main transcript	c.3165T>C	p.Leu1055=	synonymous_variant	17/41
COL18A1	NM_030582.4 linkuse as main transcript	c.2460T>C	p.Leu820=	synonymous_variant	17/41

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL18A1	ENST00000651438.1 linkuse as main transcript	c.1920T>C	p.Leu640=	synonymous_variant	18/42		NM_001379500.1		P39060-2
COL18A1	ENST00000355480.10 linkuse as main transcript	c.2460T>C	p.Leu820=	synonymous_variant	17/41	1			P39060-1
COL18A1	ENST00000359759.8 linkuse as main transcript	c.3165T>C	p.Leu1055=	synonymous_variant	17/41	5		P1	P39060-3

Frequencies

GnomAD3 genomes

AF:

0.320

AC:

48675

AN:

151910

Hom.:

7863

Cov.:

show subpopulations

Gnomad AFR

AF:

0.366

Gnomad AMI

AF:

0.204

Gnomad AMR

AF:

0.292

Gnomad ASJ

AF:

0.320

Gnomad EAS

AF:

0.243

Gnomad SAS

AF:

0.334

Gnomad FIN

AF:

0.356

Gnomad MID

AF:

0.301

Gnomad NFE

AF:

0.300

Gnomad OTH

AF:

0.324

GnomAD3 exomes

AF:

0.303

AC:

75475

AN:

249126

Hom.:

11700

AF XY:

0.304

AC XY:

41112

AN XY:

135240

show subpopulations

Gnomad AFR exome

AF:

0.373

Gnomad AMR exome

AF:

0.254

Gnomad ASJ exome

AF:

0.333

Gnomad EAS exome

AF:

0.241

Gnomad SAS exome

AF:

0.323

Gnomad FIN exome

AF:

0.343

Gnomad NFE exome

AF:

0.303

Gnomad OTH exome

AF:

0.295

GnomAD4 exome

AF:

0.305

AC:

445715

AN:

1461494

Hom.:

68501

Cov.:

AF XY:

0.305

AC XY:

221950

AN XY:

727022

show subpopulations

Gnomad4 AFR exome

AF:

0.374

Gnomad4 AMR exome

AF:

0.261

Gnomad4 ASJ exome

AF:

0.337

Gnomad4 EAS exome

AF:

0.257

Gnomad4 SAS exome

AF:

0.322

Gnomad4 FIN exome

AF:

0.329

Gnomad4 NFE exome

AF:

0.303

Gnomad4 OTH exome

AF:

0.296

GnomAD4 genome

AF:

0.320

AC:

48714

AN:

152028

Hom.:

7874

Cov.:

AF XY:

0.324

AC XY:

24095

AN XY:

74306

show subpopulations

Gnomad4 AFR

AF:

0.366

Gnomad4 AMR

AF:

0.292

Gnomad4 ASJ

AF:

0.320

Gnomad4 EAS

AF:

0.244

Gnomad4 SAS

AF:

0.334

Gnomad4 FIN

AF:

0.356

Gnomad4 NFE

AF:

0.300

Gnomad4 OTH

AF:

0.322

Alfa

AF:

0.299

Hom.:

11738

Bravo

AF:

0.317

Asia WGS

AF:

0.290

AC:

1011

AN:

3478

EpiCase

AF:

0.305

EpiControl

AF:

0.308

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Knobloch syndrome

Benign:5

Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	Jan 23, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 22, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 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, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	Jun 28, 2017	- -

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	May 04, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

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

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.83

Cadd

Benign

4.4

Dann

Benign

0.50

RBP_binding_hub_radar

1.1

RBP_regulation_power_radar

2.4

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