rs113315760

Positions:

• chr21-45512215-G-A

Variant summary

Our verdict is Benign. Variant got -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS2

The NM_001379500.1(COL18A1):​c.3837G>A​(p.Ser1279=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00156 in 1,612,118 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0011 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0016 (3 hom.)
• Consequence: COL18A1 NM_001379500.1 synonymous
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -8.40

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 -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 21-45512215-G-A is Benign according to our data. Variant chr21-45512215-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 447130.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr21-45512215-G-A is described in Lovd as [Likely_benign]. Variant chr21-45512215-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-8.4 with no splicing effect.
• BS2: High Homozygotes in GnomAdExome4 at 3 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COL18A1	NM_001379500.1	c.3837G>A	p.Ser1279=	synonymous_variant	42/42	ENST00000651438.1	NP_001366429.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COL18A1	ENST00000651438.1	c.3837G>A	p.Ser1279=	synonymous_variant	42/42		NM_001379500.1	ENSP00000498485

Frequencies

GnomAD3 genomes AF: 0.00106 AC: 162 AN: 152218 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000531

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00111

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00168

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000989 AC: 239 AN: 241570 Hom.: 0 AF XY: 0.000937 AC XY: 124 AN XY: 132374

Gnomad AFR exome AF: 0.000544

Gnomad AMR exome AF: 0.000730

Gnomad ASJ exome AF: 0.000810

Gnomad EAS exome AF: 0.000112

Gnomad SAS exome AF: 0.0000329

Gnomad FIN exome AF: 0.000241

Gnomad NFE exome AF: 0.00170

Gnomad OTH exome AF: 0.00102

GnomAD4 exome AF: 0.00161 AC: 2350 AN: 1459782 Hom.: 3 Cov.: 32 AF XY: 0.00153 AC XY: 1109 AN XY: 726200

Gnomad4 AFR exome AF: 0.000299

Gnomad4 AMR exome AF: 0.000717

Gnomad4 ASJ exome AF: 0.000920

Gnomad4 EAS exome AF: 0.0000505

Gnomad4 SAS exome AF: 0.0000464

Gnomad4 FIN exome AF: 0.000479

Gnomad4 NFE exome AF: 0.00197

Gnomad4 OTH exome AF: 0.00106

GnomAD4 genome AF: 0.00106 AC: 162 AN: 152336 Hom.: 0 Cov.: 33 AF XY: 0.00102 AC XY: 76 AN XY: 74496

Gnomad4 AFR AF: 0.000529

Gnomad4 AMR AF: 0.00111

Gnomad4 ASJ AF: 0.00144

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000941

Gnomad4 NFE AF: 0.00168

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.00145 Hom.: 0

Bravo AF: 0.00131

EpiCase AF: 0.00180

EpiControl AF: 0.00232

ClinVar

Significance: Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 25, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2024	COL18A1: BP4, BP7 -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

not specified Benign:3

Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Nov 09, 2016	- -
Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Aug 13, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	0.034
DANN	Benign	0.93
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs113315760; hg19: chr21-46932129;