rs2838952

chr21-45510249-C-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_001379500.1(COL18A1):c.3681C>T(p.Ile1227=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0319 in 1,604,708 control chromosomes in the GnomAD database, including 1,174 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.027 (88 hom., cov: 34)
  • Exomes 𝑓: 0.032 (1086 hom.)
• Consequence: COL18A1 NM_001379500.1 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -3.73

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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.43).
• BP6: Variant 21-45510249-C-T is Benign according to our data. Variant chr21-45510249-C-T is described in ClinVar as [Benign]. Clinvar id is 522315.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr21-45510249-C-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-3.73 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0706 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL18A1	NM_001379500.1	c.3681C>T	p.Ile1227=	synonymous_variant	40/42	ENST00000651438.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL18A1	ENST00000651438.1	c.3681C>T	p.Ile1227=	synonymous_variant	40/42		NM_001379500.1

Frequencies

GnomAD3 genomes AF: 0.0267 AC: 4059 AN: 152202 Hom.: 86 Cov.: 34

Gnomad AFR AF: 0.00767

Gnomad AMI AF: 0.0702

Gnomad AMR AF: 0.0736

Gnomad ASJ AF: 0.00605

Gnomad EAS AF: 0.000577

Gnomad SAS AF: 0.0170

Gnomad FIN AF: 0.0244

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0314

Gnomad OTH AF: 0.0249

GnomAD3 exomes AF: 0.0403 AC: 9068 AN: 225060 Hom.: 431 AF XY: 0.0353 AC XY: 4387 AN XY: 124106

Gnomad AFR exome AF: 0.00648

Gnomad AMR exome AF: 0.142

Gnomad ASJ exome AF: 0.00406

Gnomad EAS exome AF: 0.000238

Gnomad SAS exome AF: 0.0189

Gnomad FIN exome AF: 0.0274

Gnomad NFE exome AF: 0.0304

Gnomad OTH exome AF: 0.0294

GnomAD4 exome AF: 0.0324 AC: 47108 AN: 1452388 Hom.: 1086 Cov.: 33 AF XY: 0.0314 AC XY: 22682 AN XY: 722064

Gnomad4 AFR exome AF: 0.00521

Gnomad4 AMR exome AF: 0.130

Gnomad4 ASJ exome AF: 0.00501

Gnomad4 EAS exome AF: 0.000205

Gnomad4 SAS exome AF: 0.0202

Gnomad4 FIN exome AF: 0.0275

Gnomad4 NFE exome AF: 0.0329

Gnomad4 OTH exome AF: 0.0248

GnomAD4 genome AF: 0.0267 AC: 4071 AN: 152320 Hom.: 88 Cov.: 34 AF XY: 0.0271 AC XY: 2015 AN XY: 74490

Gnomad4 AFR AF: 0.00765

Gnomad4 AMR AF: 0.0742

Gnomad4 ASJ AF: 0.00605

Gnomad4 EAS AF: 0.000578

Gnomad4 SAS AF: 0.0174

Gnomad4 FIN AF: 0.0244

Gnomad4 NFE AF: 0.0314

Gnomad4 OTH AF: 0.0246

Alfa AF: 0.0313 Hom.: 102

Bravo AF: 0.0317

Asia WGS AF: 0.0100 AC: 38 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 22, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

Knobloch syndrome Benign:2

Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	Jan 23, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	Sep 21, 2015	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.43
Cadd	Benign	2.6
Dann	Benign	0.94
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8

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: rs2838952; hg19: chr21-46930163;