rs116618591

Variant names:

• chr21-45504408-G-A
• rs116618591
• NM_001379500.1:c.2728-8G>A

Your query was ambiguous. Multiple possible variants found:

• chr21-45504408-G-A
• chr21-45504408-G-T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001379500.1(COL18A1):​c.2728-8G>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0164 in 1,610,564 control chromosomes in the GnomAD database, including 312 homozygotes. In-silico tool predicts a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.018 (44 hom., cov: 33)
  • Exomes 𝑓: 0.016 (268 hom.)
• Consequence: COL18A1 NM_001379500.1 splice_region, intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -4.69
• Publications: 3 publications found

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

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.93).
• BP6: Variant 21-45504408-G-A is Benign according to our data. Variant chr21-45504408-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 261905.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.0182 (2771/152276) while in subpopulation SAS AF = 0.0309 (149/4828). AF 95% confidence interval is 0.0268. There are 44 homozygotes in GnomAd4. There are 1459 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 44 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL18A1	NM_001379500.1	c.2728-8G>A		splice_region_variant, intron_variant	Intron 33 of 41	ENST00000651438.1	NP_001366429.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL18A1	ENST00000651438.1	c.2728-8G>A		splice_region_variant, intron_variant	Intron 33 of 41		NM_001379500.1	ENSP00000498485.1

Frequencies

GnomAD3 genomes AF: 0.0181 AC: 2753 AN: 152158 Hom.: 44 Cov.: 33

Gnomad AFR AF: 0.0201

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0116

Gnomad ASJ AF: 0.0196

Gnomad EAS AF: 0.00328

Gnomad SAS AF: 0.0306

Gnomad FIN AF: 0.0477

Gnomad MID AF: 0.0316

Gnomad NFE AF: 0.0143

Gnomad OTH AF: 0.0120

GnomAD2 exomes AF: 0.0183 AC: 4423 AN: 241232 AF XY: 0.0198

Gnomad AFR exome AF: 0.0202

Gnomad AMR exome AF: 0.00999

Gnomad ASJ exome AF: 0.0189

Gnomad EAS exome AF: 0.00483

Gnomad FIN exome AF: 0.0419

Gnomad NFE exome AF: 0.0147

Gnomad OTH exome AF: 0.0216

GnomAD4 exome AF: 0.0162 AC: 23586 AN: 1458288 Hom.: 268 Cov.: 32 AF XY: 0.0169 AC XY: 12288 AN XY: 725360

African (AFR) AF: 0.0232 AC: 777 AN: 33422

American (AMR) AF: 0.00964 AC: 429 AN: 44514

Ashkenazi Jewish (ASJ) AF: 0.0184 AC: 478 AN: 25980

East Asian (EAS) AF: 0.00166 AC: 66 AN: 39662

South Asian (SAS) AF: 0.0303 AC: 2607 AN: 86040

European-Finnish (FIN) AF: 0.0393 AC: 2047 AN: 52040

Middle Eastern (MID) AF: 0.0348 AC: 198 AN: 5690

European-Non Finnish (NFE) AF: 0.0143 AC: 15923 AN: 1110702

Other (OTH) AF: 0.0176 AC: 1061 AN: 60238

GnomAD4 genome AF: 0.0182 AC: 2771 AN: 152276 Hom.: 44 Cov.: 33 AF XY: 0.0196 AC XY: 1459 AN XY: 74442

African (AFR) AF: 0.0205 AC: 850 AN: 41552

American (AMR) AF: 0.0116 AC: 177 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.0196 AC: 68 AN: 3472

East Asian (EAS) AF: 0.00348 AC: 18 AN: 5172

South Asian (SAS) AF: 0.0309 AC: 149 AN: 4828

European-Finnish (FIN) AF: 0.0477 AC: 506 AN: 10616

Middle Eastern (MID) AF: 0.0272 AC: 8 AN: 294

European-Non Finnish (NFE) AF: 0.0143 AC: 970 AN: 68016

Other (OTH) AF: 0.0118 AC: 25 AN: 2112

Alfa AF: 0.0141 Hom.: 28

Bravo AF: 0.0157

Asia WGS AF: 0.0170 AC: 62 AN: 3478

EpiCase AF: 0.0165

EpiControl AF: 0.0143

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

not specified Benign:2

-

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

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Knobloch syndrome Benign:1

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	0.0060
DANN	Benign	0.68
PhyloP100		-4.7
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs116618591; hg19: chr21-46924322;