rs11544970

chr21-45504469-C-Tchr21-45504469-C-G

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_001379500.1(COL18A1):c.2781C>T(p.Pro927=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0253 in 1,607,824 control chromosomes in the GnomAD database, including 640 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. P927P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.024 (53 hom., cov: 33)
  • Exomes 𝑓: 0.025 (587 hom.)
• Consequence: COL18A1 NM_001379500.1 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -4.14

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=-0.79).
• BP6: Variant 21-45504469-C-T is Benign according to our data. Variant chr21-45504469-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 261906.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr21-45504469-C-T is described in Lovd as [Benign]. Variant chr21-45504469-C-T is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-4.14 with no splicing effect.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.0237 (3586/151046) while in subpopulation SAS AF= 0.0398 (190/4778). AF 95% confidence interval is 0.0351. There are 53 homozygotes in gnomad4. There are 1832 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 52 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL18A1	NM_001379500.1	c.2781C>T	p.Pro927=	synonymous_variant	34/42	ENST00000651438.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL18A1	ENST00000651438.1	c.2781C>T	p.Pro927=	synonymous_variant	34/42		NM_001379500.1

Frequencies

GnomAD3 genomes AF: 0.0237 AC: 3582 AN: 150928 Hom.: 52 Cov.: 33

Gnomad AFR AF: 0.00837

Gnomad AMI AF: 0.0419

Gnomad AMR AF: 0.0328

Gnomad ASJ AF: 0.0531

Gnomad EAS AF: 0.0361

Gnomad SAS AF: 0.0404

Gnomad FIN AF: 0.0298

Gnomad MID AF: 0.0348

Gnomad NFE AF: 0.0259

Gnomad OTH AF: 0.0328

GnomAD3 exomes AF: 0.0291 AC: 6877 AN: 236534 Hom.: 116 AF XY: 0.0307 AC XY: 4011 AN XY: 130688

Gnomad AFR exome AF: 0.00922

Gnomad AMR exome AF: 0.0249

Gnomad ASJ exome AF: 0.0573

Gnomad EAS exome AF: 0.0312

Gnomad SAS exome AF: 0.0434

Gnomad FIN exome AF: 0.0286

Gnomad NFE exome AF: 0.0257

Gnomad OTH exome AF: 0.0349

GnomAD4 exome AF: 0.0255 AC: 37131 AN: 1456778 Hom.: 587 Cov.: 32 AF XY: 0.0264 AC XY: 19100 AN XY: 724694

Gnomad4 AFR exome AF: 0.00859

Gnomad4 AMR exome AF: 0.0266

Gnomad4 ASJ exome AF: 0.0566

Gnomad4 EAS exome AF: 0.0307

Gnomad4 SAS exome AF: 0.0428

Gnomad4 FIN exome AF: 0.0263

Gnomad4 NFE exome AF: 0.0234

Gnomad4 OTH exome AF: 0.0284

GnomAD4 genome AF: 0.0237 AC: 3586 AN: 151046 Hom.: 53 Cov.: 33 AF XY: 0.0248 AC XY: 1832 AN XY: 73806

Gnomad4 AFR AF: 0.00837

Gnomad4 AMR AF: 0.0327

Gnomad4 ASJ AF: 0.0531

Gnomad4 EAS AF: 0.0364

Gnomad4 SAS AF: 0.0398

Gnomad4 FIN AF: 0.0298

Gnomad4 NFE AF: 0.0259

Gnomad4 OTH AF: 0.0353

Alfa AF: 0.0227 Hom.: 14

Bravo AF: 0.0227

Asia WGS AF: 0.0300 AC: 103 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Knobloch syndrome Benign:3

Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	Jan 23, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Likely benign, criteria provided, single submitter	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	Sep 21, 2015	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	May 04, 2021	See Variant Classification Assertion Criteria. -

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	-0.79
Cadd	Benign	0.13
Dann	Benign	0.81
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: rs11544970; hg19: chr21-46924383; COSMIC: COSV60591302; COSMIC: COSV60591302;