Genetic Variant COL18A1:c.106+14237G>T (chr21-45419710-G-T) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_001379500.1(COL18A1):c.106+14237G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.689 in 152,112 control chromosomes in the GnomAD database, including 37,878 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.69 ( 37878 hom., cov: 34)

Exomes 𝑓: 0.71 ( 4 hom. )

Failed GnomAD Quality Control

Consequence

COL18A1
NM_001379500.1 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.404

Publications

6 publications found

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:

COL18A1-AS1 (HGNC:23132): (COL18A1 antisense RNA 1)

COL18A1-AS1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-1.05).

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.802 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein
COL18A1	NM_001379500.1 link	c.106+14237G>T	intron_variant	Intron 2 of 41	ENST00000651438.1	NP_001366429.1
COL18A1-AS1	NR_027498.1 link	n.*6C>A	downstream_gene_variant
COL18A1-AS1	NR_028082.1 link	n.*6C>A	downstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein	UniProt
COL18A1	ENST00000651438.1 link	c.106+14237G>T	intron_variant	Intron 2 of 41		NM_001379500.1	ENSP00000498485.1	P39060-2
COL18A1-AS1	ENST00000397787.5 link	n.*6C>A	downstream_gene_variant		1
COL18A1-AS1	ENST00000485206.1 link	n.*6C>A	downstream_gene_variant		1

Frequencies

GnomAD3 genomes

AF:

0.689

AC:

104792

AN:

151994

Hom.:

37876

Cov.:

show subpopulations

Gnomad AFR

AF:

0.475

Gnomad AMI

AF:

0.760

Gnomad AMR

AF:

0.659

Gnomad ASJ

AF:

0.839

Gnomad EAS

AF:

0.495

Gnomad SAS

AF:

0.729

Gnomad FIN

AF:

0.825

Gnomad MID

AF:

0.796

Gnomad NFE

AF:

0.808

Gnomad OTH

AF:

0.701

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.714

AC:

AN:

Hom.:

Cov.:

AF XY:

0.875

AC XY:

AN XY:

show subpopulations

African (AFR)

AC:

AN:

American (AMR)

AC:

AN:

Ashkenazi Jewish (ASJ)

AC:

AN:

East Asian (EAS)

AC:

AN:

South Asian (SAS)

AC:

AN:

European-Finnish (FIN)

AF:

1.00

AC:

AN:

Middle Eastern (MID)

AC:

AN:

European-Non Finnish (NFE)

AF:

0.600

AC:

AN:

Other (OTH)

AF:

1.00

AC:

AN:

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.689

AC:

104827

AN:

152112

Hom.:

37878

Cov.:

AF XY:

0.687

AC XY:

51113

AN XY:

74378

show subpopulations

African (AFR)

AF:

0.475

AC:

19680

AN:

41468

American (AMR)

AF:

0.658

AC:

10058

AN:

15282

Ashkenazi Jewish (ASJ)

AF:

0.839

AC:

2911

AN:

3468

East Asian (EAS)

AF:

0.495

AC:

2563

AN:

5180

South Asian (SAS)

AF:

0.730

AC:

3522

AN:

4824

European-Finnish (FIN)

AF:

0.825

AC:

8743

AN:

10594

Middle Eastern (MID)

AF:

0.795

AC:

232

AN:

292

European-Non Finnish (NFE)

AF:

0.808

AC:

54941

AN:

67984

Other (OTH)

AF:

0.704

AC:

1484

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

1494

2988

4482

5976

7470

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.776

Hom.:

65071

Bravo

AF:

0.669

Asia WGS

AF:

0.615

AC:

2138

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-1.1

CADD

Benign

0.19

(source)

DANN

Benign

0.23

PhyloP100

-0.40

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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21-45419710-G-T

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over