rs12483761

Positions:

• chr21-45507575-A-G
• chr21-45507575-A-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001379500.1(COL18A1):​c.3231A>G​(p.Thr1077=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.127 in 1,611,882 control chromosomes in the GnomAD database, including 13,605 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.14 (1533 hom., cov: 33)
  • Exomes 𝑓: 0.13 (12072 hom.)
• Consequence: COL18A1 NM_001379500.1 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -3.53

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.0).
• BP6: Variant 21-45507575-A-G is Benign according to our data. Variant chr21-45507575-A-G is described in ClinVar as [Benign]. Clinvar id is 261908.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr21-45507575-A-G is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-3.53 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.18 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL18A1	NM_001379500.1	c.3231A>G	p.Thr1077=	synonymous_variant	38/42	ENST00000651438.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL18A1	ENST00000651438.1	c.3231A>G	p.Thr1077=	synonymous_variant	38/42		NM_001379500.1

Frequencies

GnomAD3 genomes AF: 0.139 AC: 21095 AN: 152010 Hom.: 1529 Cov.: 33

Gnomad AFR AF: 0.150

Gnomad AMI AF: 0.0932

Gnomad AMR AF: 0.185

Gnomad ASJ AF: 0.129

Gnomad EAS AF: 0.0169

Gnomad SAS AF: 0.0812

Gnomad FIN AF: 0.161

Gnomad MID AF: 0.0949

Gnomad NFE AF: 0.132

Gnomad OTH AF: 0.147

GnomAD3 exomes AF: 0.125 AC: 30724 AN: 246296 Hom.: 2047 AF XY: 0.122 AC XY: 16383 AN XY: 134198

Gnomad AFR exome AF: 0.147

Gnomad AMR exome AF: 0.176

Gnomad ASJ exome AF: 0.127

Gnomad EAS exome AF: 0.0163

Gnomad SAS exome AF: 0.0849

Gnomad FIN exome AF: 0.158

Gnomad NFE exome AF: 0.127

Gnomad OTH exome AF: 0.132

GnomAD4 exome AF: 0.126 AC: 183711 AN: 1459754 Hom.: 12072 Cov.: 33 AF XY: 0.125 AC XY: 90455 AN XY: 726162

Gnomad4 AFR exome AF: 0.146

Gnomad4 AMR exome AF: 0.182

Gnomad4 ASJ exome AF: 0.125

Gnomad4 EAS exome AF: 0.0111

Gnomad4 SAS exome AF: 0.0880

Gnomad4 FIN exome AF: 0.161

Gnomad4 NFE exome AF: 0.129

Gnomad4 OTH exome AF: 0.125

GnomAD4 genome AF: 0.139 AC: 21112 AN: 152128 Hom.: 1533 Cov.: 33 AF XY: 0.138 AC XY: 10255 AN XY: 74372

Gnomad4 AFR AF: 0.150

Gnomad4 AMR AF: 0.185

Gnomad4 ASJ AF: 0.129

Gnomad4 EAS AF: 0.0168

Gnomad4 SAS AF: 0.0802

Gnomad4 FIN AF: 0.161

Gnomad4 NFE AF: 0.132

Gnomad4 OTH AF: 0.146

Alfa AF: 0.133 Hom.: 1038

Bravo AF: 0.141

Asia WGS AF: 0.0550 AC: 190 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 19, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	May 07, 2018	- -

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	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	0.17
DANN	Benign	0.61
RBP_binding_hub_radar		1.1
RBP_regulation_power_radar		3.2

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: rs12483761; hg19: chr21-46927489; COSMIC: COSV60587897; COSMIC: COSV60587897;