dbSNP rs61735029: COL18A1:p.Gln49Leu (chr21-45455676-A-T) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_130444.3(COL18A1):c.146A>T(p.Gln49Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00225 in 1,613,820 control chromosomes in the GnomAD database, including 62 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.012 ( 29 hom., cov: 33)

Exomes 𝑓: 0.0013 ( 33 hom. )

Consequence

COL18A1
NM_130444.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: -2.02

Publications

3 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 Gene-Disease associations (from GenCC):

Knobloch syndrome 1
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: ClinGen, G2P, Labcorp Genetics (formerly Invitae)
Knobloch syndrome
Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Laboratory for Molecular Medicine, Orphanet
hereditary glaucoma, primary closed-angle
Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

COL18A1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.003584385).

BP6

Variant 21-45455676-A-T is Benign according to our data. Variant chr21-45455676-A-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 445671.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0116 (1772/152294) while in subpopulation AFR AF = 0.0405 (1682/41560). AF 95% confidence interval is 0.0389. There are 29 homozygotes in GnomAd4. There are 850 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 29 AD,AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_130444.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
COL18A1	NM_001379500.1	MANE Select	c.107-12566A>T		intron	N/A	NP_001366429.1	P39060-2
COL18A1	NM_130444.3		c.146A>T	p.Gln49Leu	missense	Exon 1 of 41	NP_569711.2
COL18A1	NM_030582.4		c.146A>T	p.Gln49Leu	missense	Exon 1 of 41	NP_085059.2	A0AAG2UXZ5

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
COL18A1	ENST00000355480.10	TSL:1	c.146A>T	p.Gln49Leu	missense	Exon 1 of 41	ENSP00000347665.5	P39060-1
COL18A1	ENST00000651438.1	MANE Select	c.107-12566A>T		intron	N/A	ENSP00000498485.1	P39060-2
COL18A1	ENST00000359759.8	TSL:5	c.146A>T	p.Gln49Leu	missense	Exon 1 of 41	ENSP00000352798.4	P39060-3

Frequencies

GnomAD3 genomes

AF:

0.0116

AC:

1769

AN:

152176

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0405

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00366

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000220

Gnomad OTH

AF:

0.00860

GnomAD2 exomes

AF:

0.00300

AC:

749

AN:

249388

AF XY:

0.00222

show subpopulations

Gnomad AFR exome

AF:

0.0420

Gnomad AMR exome

AF:

0.00180

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000265

Gnomad OTH exome

AF:

0.000825

GnomAD4 exome

AF:

0.00127

AC:

1855

AN:

1461526

Hom.:

Cov.:

AF XY:

0.00112

AC XY:

815

AN XY:

727088

show subpopulations

African (AFR)

AF:

0.0418

AC:

1398

AN:

33478

American (AMR)

AF:

0.00228

AC:

102

AN:

44666

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26128

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.000116

AC:

AN:

86256

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53184

Middle Eastern (MID)

AF:

0.00277

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000139

AC:

155

AN:

1111952

Other (OTH)

AF:

0.00288

AC:

174

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.493

Heterozygous variant carriers

122

244

367

489

611

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

104

156

208

260

<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:

0.0116

AC:

1772

AN:

152294

Hom.:

Cov.:

AF XY:

0.0114

AC XY:

850

AN XY:

74454

show subpopulations

African (AFR)

AF:

0.0405

AC:

1682

AN:

41560

American (AMR)

AF:

0.00366

AC:

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5174

South Asian (SAS)

AF:

0.000207

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000221

AC:

AN:

68022

Other (OTH)

AF:

0.00851

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

186

279

372

465

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.00354

Hom.:

Bravo

AF:

0.0130

ESP6500AA

AF:

0.0362

AC:

151

ESP6500EA

AF:

0.000118

AC:

ExAC

AF:

0.00377

AC:

457

Asia WGS

AF:

0.00173

AC:

AN:

3478

EpiCase

AF:

0.0000545

EpiControl

AF:

0.000415

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.095

BayesDel_addAF

Benign

-0.71

BayesDel_noAF

Benign

-0.76

CADD

Benign

0.57

(source)

DANN

Benign

0.86

DEOGEN2

Benign

0.052

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.4

FATHMM_MKL

Benign

0.055

LIST_S2

Benign

0.24

MetaRNN

Benign

0.0036

MetaSVM

Benign

-1.1

PhyloP100

-2.0

PrimateAI

Benign

0.26

PROVEAN

Benign

-1.7

REVEL

Benign

0.14

Sift

Benign

0.050

Sift4G

Benign

0.16

Polyphen

0.0030

Vest4

0.13

MVP

0.22

MPC

0.066

ClinPred

0.0027

GERP RS

-6.7

PromoterAI

-0.0049

Neutral

(source)

Varity_R

0.049

gMVP

0.076

Mutation Taster

=96/4

polymorphism

(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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over