rs7499

Variant names:

• chr21-45512414-G-A
• rs7499
• NM_001379500.1:c.*16G>A

Your query was ambiguous. Multiple possible variants found:

• chr21-45512414-G-A
• chr21-45512414-G-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001379500.1(COL18A1):​c.*16G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.407 in 1,608,724 control chromosomes in the GnomAD database, including 134,572 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.42 (13265 hom., cov: 33)
  • Exomes 𝑓: 0.41 (121307 hom.)
• Consequence: COL18A1 NM_001379500.1 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -2.08

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant 21-45512414-G-A is Benign according to our data. Variant chr21-45512414-G-A is described in ClinVar as [Benign]. Clinvar id is 261884.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr21-45512414-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.555 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL18A1	NM_001379500.1	c.*16G>A		3_prime_UTR_variant	Exon 42 of 42	ENST00000651438.1	NP_001366429.1
SLC19A1	NM_194255.4	c.*3244C>T		downstream_gene_variant		ENST00000311124.9	NP_919231.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL18A1	ENST00000651438.1	c.*16G>A		3_prime_UTR_variant	Exon 42 of 42		NM_001379500.1	ENSP00000498485.1
SLC19A1	ENST00000311124.9	c.*3244C>T		downstream_gene_variant		1	NM_194255.4	ENSP00000308895.4

Frequencies

GnomAD3 genomes AF: 0.416 AC: 63233 AN: 151950 Hom.: 13255 Cov.: 33

Gnomad AFR AF: 0.439

Gnomad AMI AF: 0.388

Gnomad AMR AF: 0.404

Gnomad ASJ AF: 0.379

Gnomad EAS AF: 0.572

Gnomad SAS AF: 0.426

Gnomad FIN AF: 0.412

Gnomad MID AF: 0.449

Gnomad NFE AF: 0.394

Gnomad OTH AF: 0.438

GnomAD3 exomes AF: 0.419 AC: 100466 AN: 239992 Hom.: 21123 AF XY: 0.416 AC XY: 54543 AN XY: 131108

Gnomad AFR exome AF: 0.446

Gnomad AMR exome AF: 0.420

Gnomad ASJ exome AF: 0.383

Gnomad EAS exome AF: 0.570

Gnomad SAS exome AF: 0.419

Gnomad FIN exome AF: 0.404

Gnomad NFE exome AF: 0.396

Gnomad OTH exome AF: 0.429

GnomAD4 exome AF: 0.406 AC: 590934 AN: 1456656 Hom.: 121307 Cov.: 37 AF XY: 0.405 AC XY: 293592 AN XY: 724348

Gnomad4 AFR exome AF: 0.448

Gnomad4 AMR exome AF: 0.420

Gnomad4 ASJ exome AF: 0.386

Gnomad4 EAS exome AF: 0.601

Gnomad4 SAS exome AF: 0.419

Gnomad4 FIN exome AF: 0.402

Gnomad4 NFE exome AF: 0.396

Gnomad4 OTH exome AF: 0.414

GnomAD4 genome AF: 0.416 AC: 63260 AN: 152068 Hom.: 13265 Cov.: 33 AF XY: 0.420 AC XY: 31179 AN XY: 74322

Gnomad4 AFR AF: 0.439

Gnomad4 AMR AF: 0.403

Gnomad4 ASJ AF: 0.379

Gnomad4 EAS AF: 0.573

Gnomad4 SAS AF: 0.427

Gnomad4 FIN AF: 0.412

Gnomad4 NFE AF: 0.394

Gnomad4 OTH AF: 0.436

Alfa AF: 0.402 Hom.: 16202

Bravo AF: 0.417

Asia WGS AF: 0.486 AC: 1689 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Knobloch syndrome Benign:4

Jul 22, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

May 31, 2017

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:2

Feb 23, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 22461898, 21118967) -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

not specified Benign:1

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary glaucoma, primary closed-angle Benign:1

Jul 22, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	0.17
DANN	Benign	0.80
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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: rs7499; hg19: chr21-46932328; COSMIC: COSV60589997; COSMIC: COSV60589997;