rs2230689

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

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

The NM_001379500.1(COL18A1):c.1143G>A(p.Ala381Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00835 in 1,562,254 control chromosomes in the GnomAD database, including 275 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0069 ( 30 hom., cov: 33)

Exomes 𝑓: 0.0085 ( 245 hom. )

Consequence

COL18A1
NM_001379500.1 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: -0.773

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=-0.81).

BP6

Variant 21-45477887-G-A is Benign according to our data. Variant chr21-45477887-G-A is described in ClinVar as [Benign]. Clinvar id is 261889.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr21-45477887-G-A is described in Lovd as [Likely_benign].

BP7

Synonymous conserved (PhyloP=-0.773 with no splicing effect.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0698 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL18A1	NM_001379500.1 link	c.1143G>A	p.Ala381Ala	synonymous_variant	Exon 8 of 42	ENST00000651438.1	NP_001366429.1
COL18A1	NM_130444.3 link	c.2388G>A	p.Ala796Ala	synonymous_variant	Exon 7 of 41		NP_569711.2	P39060
COL18A1	NM_030582.4 link	c.1683G>A	p.Ala561Ala	synonymous_variant	Exon 7 of 41		NP_085059.2	P39060D3DSM5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
COL18A1	ENST00000651438.1 link	c.1143G>A	p.Ala381Ala	synonymous_variant	Exon 8 of 42		NM_001379500.1	ENSP00000498485.1	P39060-2
COL18A1	ENST00000355480.10 link	c.1683G>A	p.Ala561Ala	synonymous_variant	Exon 7 of 41	1		ENSP00000347665.5	P39060-1
COL18A1	ENST00000359759.8 link	c.2388G>A	p.Ala796Ala	synonymous_variant	Exon 7 of 41	5		ENSP00000352798.4	P39060-3

Frequencies

GnomAD3 genomes

AF:

0.00690

AC:

1050

AN:

152208

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00166

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00373

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.0763

Gnomad SAS

AF:

0.0449

Gnomad FIN

AF:

0.00132

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00426

Gnomad OTH

AF:

0.00335

GnomAD3 exomes

AF:

0.0142

AC:

2402

AN:

169700

Hom.:

AF XY:

0.0154

AC XY:

1407

AN XY:

91126

show subpopulations

Gnomad AFR exome

AF:

0.000789

Gnomad AMR exome

AF:

0.00157

Gnomad ASJ exome

AF:

0.00161

Gnomad EAS exome

AF:

0.0861

Gnomad SAS exome

AF:

0.0397

Gnomad FIN exome

AF:

0.00155

Gnomad NFE exome

AF:

0.00420

Gnomad OTH exome

AF:

0.00648

GnomAD4 exome

AF:

0.00851

AC:

11995

AN:

1409928

Hom.:

245

Cov.:

AF XY:

0.00922

AC XY:

6427

AN XY:

696882

show subpopulations

Gnomad4 AFR exome

AF:

0.000936

Gnomad4 AMR exome

AF:

0.00154

Gnomad4 ASJ exome

AF:

0.00178

Gnomad4 EAS exome

AF:

0.0877

Gnomad4 SAS exome

AF:

0.0383

Gnomad4 FIN exome

AF:

0.00120

Gnomad4 NFE exome

AF:

0.00457

Gnomad4 OTH exome

AF:

0.00977

GnomAD4 genome

AF:

0.00687

AC:

1046

AN:

152326

Hom.:

Cov.:

AF XY:

0.00777

AC XY:

579

AN XY:

74480

show subpopulations

Gnomad4 AFR

AF:

0.00166

Gnomad4 AMR

AF:

0.00372

Gnomad4 ASJ

AF:

0.000288

Gnomad4 EAS

AF:

0.0760

Gnomad4 SAS

AF:

0.0445

Gnomad4 FIN

AF:

0.00132

Gnomad4 NFE

AF:

0.00426

Gnomad4 OTH

AF:

0.00331

Alfa

AF:

0.00434

Hom.:

Bravo

AF:

0.00603

Asia WGS

AF:

0.0480

AC:

166

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Breakthrough Genomics, Breakthrough Genomics

Significance: 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

- -

May 04, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified

Benign:2

Feb 12, 2024

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Knobloch syndrome

Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.81

CADD

Benign

5.8

DANN

Benign

0.45

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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