Genetic Variant COL18A1:c.3216+671C>T (chr21-45506637-C-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.3216+671C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.183 in 169,318 control chromosomes in the GnomAD database, including 2,968 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 0.19 ( 2736 hom., cov: 33)

Exomes 𝑓: 0.15 ( 232 hom. )

Consequence

COL18A1
NM_001379500.1 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -3.07

Publications

12 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:

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:

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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=-1.06).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.214 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL18A1	NM_001379500.1 link	c.3216+671C>T		intron_variant	Intron 37 of 41	ENST00000651438.1	NP_001366429.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL18A1	ENST00000651438.1 link	c.3216+671C>T		intron_variant	Intron 37 of 41		NM_001379500.1	ENSP00000498485.1		P39060-2

Frequencies

GnomAD3 genomes

AF:

0.187

AC:

28457

AN:

152048

Hom.:

2730

Cov.:

show subpopulations

Gnomad AFR

AF:

0.218

Gnomad AMI

AF:

0.118

Gnomad AMR

AF:

0.209

Gnomad ASJ

AF:

0.170

Gnomad EAS

AF:

0.0553

Gnomad SAS

AF:

0.149

Gnomad FIN

AF:

0.214

Gnomad MID

AF:

0.206

Gnomad NFE

AF:

0.174

Gnomad OTH

AF:

0.188

GnomAD4 exome

AF:

0.150

AC:

2568

AN:

17152

Hom.:

232

Cov.:

AF XY:

0.152

AC XY:

1377

AN XY:

9088

show subpopulations

African (AFR)

AF:

0.216

AC:

AN:

342

American (AMR)

AF:

0.190

AC:

591

AN:

3116

Ashkenazi Jewish (ASJ)

AF:

0.169

AC:

AN:

160

East Asian (EAS)

AF:

0.0461

AC:

AN:

1368

South Asian (SAS)

AF:

0.141

AC:

356

AN:

2518

European-Finnish (FIN)

AF:

0.158

AC:

AN:

304

Middle Eastern (MID)

AF:

0.233

AC:

AN:

European-Non Finnish (NFE)

AF:

0.151

AC:

1302

AN:

8606

Other (OTH)

AF:

0.141

AC:

100

AN:

708

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

100

200

299

399

499

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

150

200

250

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.187

AC:

28482

AN:

152166

Hom.:

2736

Cov.:

AF XY:

0.187

AC XY:

13911

AN XY:

74416

show subpopulations

African (AFR)

AF:

0.218

AC:

9056

AN:

41506

American (AMR)

AF:

0.209

AC:

3197

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.170

AC:

591

AN:

3472

East Asian (EAS)

AF:

0.0552

AC:

286

AN:

5180

South Asian (SAS)

AF:

0.148

AC:

713

AN:

4832

European-Finnish (FIN)

AF:

0.214

AC:

2265

AN:

10598

Middle Eastern (MID)

AF:

0.211

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.174

AC:

11809

AN:

67960

Other (OTH)

AF:

0.187

AC:

395

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

1179

2359

3538

4718

5897

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

296

592

888

1184

1480

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.177

Hom.:

8873

Bravo

AF:

0.187

Asia WGS

AF:

0.110

AC:

383

AN:

3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-1.1

CADD

Benign

0.71

(source)

DANN

Benign

0.57

PhyloP100

-3.1

RBP_binding_hub_radar

0.92

RBP_regulation_power_radar

2.1

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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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