21-45504408-G-A

Position:

chr21-45504408-G-A

Variant summary

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

The NM_001379500.1(COL18A1):c.2728-8G>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0164 in 1,610,564 control chromosomes in the GnomAD database, including 312 homozygotes. In-silico tool predicts a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.018 ( 44 hom., cov: 33)

Exomes 𝑓: 0.016 ( 268 hom. )

Consequence

COL18A1
NM_001379500.1 splice_region, intron

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: -4.69

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:

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 (BayesDel_noAF=-0.93).

BP6

Variant 21-45504408-G-A is Benign according to our data. Variant chr21-45504408-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 261905.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr21-45504408-G-A is described in Lovd as [Benign]. Variant chr21-45504408-G-A is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.0182 (2771/152276) while in subpopulation SAS AF= 0.0309 (149/4828). AF 95% confidence interval is 0.0268. There are 44 homozygotes in gnomad4. There are 1459 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 44 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COL18A1	NM_001379500.1 link	c.2728-8G>A		splice_region_variant, intron_variant		ENST00000651438.1	NP_001366429.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COL18A1	ENST00000651438.1 link	c.2728-8G>A		splice_region_variant, intron_variant			NM_001379500.1	ENSP00000498485.1		P39060-2

Frequencies

GnomAD3 genomes

AF:

0.0181

AC:

2753

AN:

152158

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0201

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0116

Gnomad ASJ

AF:

0.0196

Gnomad EAS

AF:

0.00328

Gnomad SAS

AF:

0.0306

Gnomad FIN

AF:

0.0477

Gnomad MID

AF:

0.0316

Gnomad NFE

AF:

0.0143

Gnomad OTH

AF:

0.0120

GnomAD3 exomes

AF:

0.0183

AC:

4423

AN:

241232

Hom.:

AF XY:

0.0198

AC XY:

2626

AN XY:

132696

show subpopulations

Gnomad AFR exome

AF:

0.0202

Gnomad AMR exome

AF:

0.00999

Gnomad ASJ exome

AF:

0.0189

Gnomad EAS exome

AF:

0.00483

Gnomad SAS exome

AF:

0.0305

Gnomad FIN exome

AF:

0.0419

Gnomad NFE exome

AF:

0.0147

Gnomad OTH exome

AF:

0.0216

GnomAD4 exome

AF:

0.0162

AC:

23586

AN:

1458288

Hom.:

268

Cov.:

AF XY:

0.0169

AC XY:

12288

AN XY:

725360

show subpopulations

Gnomad4 AFR exome

AF:

0.0232

Gnomad4 AMR exome

AF:

0.00964

Gnomad4 ASJ exome

AF:

0.0184

Gnomad4 EAS exome

AF:

0.00166

Gnomad4 SAS exome

AF:

0.0303

Gnomad4 FIN exome

AF:

0.0393

Gnomad4 NFE exome

AF:

0.0143

Gnomad4 OTH exome

AF:

0.0176

GnomAD4 genome

AF:

0.0182

AC:

2771

AN:

152276

Hom.:

Cov.:

AF XY:

0.0196

AC XY:

1459

AN XY:

74442

show subpopulations

Gnomad4 AFR

AF:

0.0205

Gnomad4 AMR

AF:

0.0116

Gnomad4 ASJ

AF:

0.0196

Gnomad4 EAS

AF:

0.00348

Gnomad4 SAS

AF:

0.0309

Gnomad4 FIN

AF:

0.0477

Gnomad4 NFE

AF:

0.0143

Gnomad4 OTH

AF:

0.0118

Alfa

AF:

0.0130

Hom.:

Bravo

AF:

0.0157

Asia WGS

AF:

0.0170

AC:

AN:

3478

EpiCase

AF:

0.0165

EpiControl

AF:

0.0143

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -

not specified

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

Knobloch syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

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

-0.93

CADD

Benign

0.0060

DANN

Benign

0.68

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