rs117866003

chr21-45512168-C-T

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_001379500.1(COL18A1):c.3810-20C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00368 in 1,603,690 control chromosomes in the GnomAD database, including 21 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0023 (1 hom., cov: 33)
  • Exomes 𝑓: 0.0038 (20 hom.)
• Consequence: COL18A1 NM_001379500.1 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -2.21

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 -16 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 21-45512168-C-T is Benign according to our data. Variant chr21-45512168-C-T is described in ClinVar as [Benign]. Clinvar id is 261918.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr21-45512168-C-T is described in Lovd as [Benign].
• BS2: High Homozygotes in GnomAdExome at 2 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL18A1	NM_001379500.1	c.3810-20C>T		intron_variant		ENST00000651438.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL18A1	ENST00000651438.1	c.3810-20C>T		intron_variant			NM_001379500.1

Frequencies

GnomAD3 genomes AF: 0.00231 AC: 351 AN: 152192 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.00113

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00190

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.000377

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00387

Gnomad OTH AF: 0.00239

GnomAD3 exomes AF: 0.00210 AC: 476 AN: 227118 Hom.: 2 AF XY: 0.00210 AC XY: 261 AN XY: 124328

Gnomad AFR exome AF: 0.00120

Gnomad AMR exome AF: 0.00227

Gnomad ASJ exome AF: 0.000208

Gnomad EAS exome AF: 0.000120

Gnomad SAS exome AF: 0.000243

Gnomad FIN exome AF: 0.000103

Gnomad NFE exome AF: 0.00358

Gnomad OTH exome AF: 0.00216

GnomAD4 exome AF: 0.00382 AC: 5548 AN: 1451380 Hom.: 20 Cov.: 32 AF XY: 0.00369 AC XY: 2660 AN XY: 721310

Gnomad4 AFR exome AF: 0.000934

Gnomad4 AMR exome AF: 0.00246

Gnomad4 ASJ exome AF: 0.000463

Gnomad4 EAS exome AF: 0.0000769

Gnomad4 SAS exome AF: 0.000354

Gnomad4 FIN exome AF: 0.000426

Gnomad4 NFE exome AF: 0.00469

Gnomad4 OTH exome AF: 0.00255

GnomAD4 genome AF: 0.00230 AC: 351 AN: 152310 Hom.: 1 Cov.: 33 AF XY: 0.00213 AC XY: 159 AN XY: 74484

Gnomad4 AFR AF: 0.00113

Gnomad4 AMR AF: 0.00189

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.000377

Gnomad4 NFE AF: 0.00387

Gnomad4 OTH AF: 0.00237

Alfa AF: 0.00177 Hom.: 0

Bravo AF: 0.00261

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

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	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
Cadd	Benign	0.070
Dann	Benign	0.70

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

Other links and lift over

dbSNP: rs117866003; hg19: chr21-46932082;