chr21-45505438-GTC-G

Position:

• chr21-45505438-GTC-G

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BS1 BS2

The NM_001379500.1(COL18A1):​c.3087+9_3087+10del variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0166 in 1,510,956 control chromosomes in the GnomAD database, including 341 homozygotes. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.019 (50 hom., cov: 34)
  • Exomes 𝑓: 0.016 (291 hom.)
• Consequence: COL18A1 NM_001379500.1 splice_region, intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.246

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]

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]

ACMG classification

Verdict is Benign. Variant got -8 ACMG points.

• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.0191 (2913/152308) while in subpopulation SAS AF= 0.0377 (182/4832). AF 95% confidence interval is 0.0332. There are 50 homozygotes in gnomad4. There are 1542 alleles in male gnomad4 subpopulation. Median coverage is 34. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 50 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COL18A1	NM_001379500.1	c.3087+9_3087+10del		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	c.3087+9_3087+10del		splice_region_variant, intron_variant			NM_001379500.1	ENSP00000498485

Frequencies

GnomAD3 genomes AF: 0.0190 AC: 2899 AN: 152192 Hom.: 48 Cov.: 34

Gnomad AFR AF: 0.0191

Gnomad AMI AF: 0.0242

Gnomad AMR AF: 0.0121

Gnomad ASJ AF: 0.0176

Gnomad EAS AF: 0.00404

Gnomad SAS AF: 0.0376

Gnomad FIN AF: 0.0478

Gnomad MID AF: 0.0601

Gnomad NFE AF: 0.0159

Gnomad OTH AF: 0.0124

GnomAD3 exomes AF: 0.0206 AC: 4013 AN: 195062 Hom.: 69 AF XY: 0.0223 AC XY: 2371 AN XY: 106238

Gnomad AFR exome AF: 0.0195

Gnomad AMR exome AF: 0.0110

Gnomad ASJ exome AF: 0.0194

Gnomad EAS exome AF: 0.00436

Gnomad SAS exome AF: 0.0386

Gnomad FIN exome AF: 0.0425

Gnomad NFE exome AF: 0.0165

Gnomad OTH exome AF: 0.0245

GnomAD4 exome AF: 0.0163 AC: 22193 AN: 1358648 Hom.: 291 AF XY: 0.0172 AC XY: 11677 AN XY: 677534

Gnomad4 AFR exome AF: 0.0208

Gnomad4 AMR exome AF: 0.0106

Gnomad4 ASJ exome AF: 0.0169

Gnomad4 EAS exome AF: 0.00171

Gnomad4 SAS exome AF: 0.0359

Gnomad4 FIN exome AF: 0.0388

Gnomad4 NFE exome AF: 0.0141

Gnomad4 OTH exome AF: 0.0183

GnomAD4 genome AF: 0.0191 AC: 2913 AN: 152308 Hom.: 50 Cov.: 34 AF XY: 0.0207 AC XY: 1542 AN XY: 74470

Gnomad4 AFR AF: 0.0194

Gnomad4 AMR AF: 0.0121

Gnomad4 ASJ AF: 0.0176

Gnomad4 EAS AF: 0.00425

Gnomad4 SAS AF: 0.0377

Gnomad4 FIN AF: 0.0478

Gnomad4 NFE AF: 0.0159

Gnomad4 OTH AF: 0.0123

Alfa AF: 0.0162 Hom.: 5

Bravo AF: 0.0162

Asia WGS AF: 0.0170 AC: 62 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2024	COL18A1: BS1, BS2; SLC19A1: BS1, BS2 -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 30, 2024	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -

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	-	- -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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

Other links and lift over

dbSNP: rs373823632; hg19: chr21-46925352;