21-45455586-C-T

Position:

chr21-45455586-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_130444.3(COL18A1):c.56C>T(p.Ala19Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00112 in 1,613,930 control chromosomes in the GnomAD database, including 23 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0060 ( 14 hom., cov: 34)

Exomes 𝑓: 0.00062 ( 9 hom. )

Consequence

COL18A1
NM_130444.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: -2.00

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.003536135).

BP6

Variant 21-45455586-C-T is Benign according to our data. Variant chr21-45455586-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 445614.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr21-45455586-C-T is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00597 (910/152356) while in subpopulation AFR AF= 0.0206 (855/41576). AF 95% confidence interval is 0.0194. There are 14 homozygotes in gnomad4. There are 405 alleles in male gnomad4 subpopulation. Median coverage is 34. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 14 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COL18A1	NM_001379500.1 linkuse as main transcript	c.107-12656C>T		intron_variant		ENST00000651438.1	NP_001366429.1
COL18A1	NM_130444.3 linkuse as main transcript	c.56C>T	p.Ala19Val	missense_variant	1/41		NP_569711.2	P39060
COL18A1	NM_030582.4 linkuse as main transcript	c.56C>T	p.Ala19Val	missense_variant	1/41		NP_085059.2	P39060D3DSM5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
COL18A1	ENST00000355480.10 linkuse as main transcript	c.56C>T	p.Ala19Val	missense_variant	1/41	1		ENSP00000347665.5	P39060-1
COL18A1	ENST00000651438.1 linkuse as main transcript	c.107-12656C>T		intron_variant			NM_001379500.1	ENSP00000498485.1	P39060-2
COL18A1	ENST00000359759.8 linkuse as main transcript	c.56C>T	p.Ala19Val	missense_variant	1/41	5		ENSP00000352798.4	P39060-3

Frequencies

GnomAD3 genomes

AF:

0.00592

AC:

902

AN:

152238

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0204

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00268

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.0000882

Gnomad OTH

AF:

0.00334

GnomAD3 exomes

AF:

0.00139

AC:

347

AN:

249084

Hom.:

AF XY:

0.00105

AC XY:

142

AN XY:

135270

show subpopulations

Gnomad AFR exome

AF:

0.0198

Gnomad AMR exome

AF:

0.000898

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000708

Gnomad OTH exome

AF:

0.000496

GnomAD4 exome

AF:

0.000616

AC:

901

AN:

1461574

Hom.:

Cov.:

AF XY:

0.000512

AC XY:

372

AN XY:

727104

show subpopulations

Gnomad4 AFR exome

AF:

0.0220

Gnomad4 AMR exome

AF:

0.00101

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000696

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000225

Gnomad4 OTH exome

AF:

0.00141

GnomAD4 genome

AF:

0.00597

AC:

910

AN:

152356

Hom.:

Cov.:

AF XY:

0.00544

AC XY:

405

AN XY:

74498

show subpopulations

Gnomad4 AFR

AF:

0.0206

Gnomad4 AMR

AF:

0.00268

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000882

Gnomad4 OTH

AF:

0.00331

Alfa

AF:

0.000963

Hom.:

Bravo

AF:

0.00666

ESP6500AA

AF:

0.0163

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.00169

AC:

204

Asia WGS

AF:

0.00144

AC:

AN:

3478

EpiCase

AF:

0.0000545

EpiControl

AF:

0.0000593

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Mar 10, 2017	- -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

Athena Diagnostics

Jun 27, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.71

BayesDel_noAF

Benign

-0.78

CADD

Benign

1.9

DANN

Benign

0.52

DEOGEN2

Benign

0.037

.;T

Eigen

Benign

-1.5

Eigen_PC

Benign

-1.5

FATHMM_MKL

Benign

0.030

LIST_S2

Benign

0.35

T;T

MetaRNN

Benign

0.0035

T;T

MetaSVM

Benign

-1.0

PrimateAI

Benign

0.42

PROVEAN

Benign

-0.91

N;N

REVEL

Benign

0.034

Sift

Uncertain

0.019

D;D

Sift4G

Benign

0.52

T;T

Polyphen

0.0010

B;B

Vest4

0.13

MVP

0.14

MPC

0.067

ClinPred

0.010

GERP RS

-0.95

Varity_R

0.050

gMVP

0.055

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