rs377715562

chr21-45509341-G-A

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_001379500.1(COL18A1):c.3250-15G>A variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00199 in 1,543,552 control chromosomes in the GnomAD database, including 20 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0022 (2 hom., cov: 33)
  • Exomes 𝑓: 0.0020 (18 hom.)
• Consequence: COL18A1 NM_001379500.1 splice_polypyrimidine_tract, intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.789

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 -16 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 21-45509341-G-A is Benign according to our data. Variant chr21-45509341-G-A is described in ClinVar as [Benign]. Clinvar id is 261909.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr21-45509341-G-A is described in Lovd as [Likely_benign]. Variant chr21-45509341-G-A is described in Lovd as [Benign].
• BS2: High Homozygotes in GnomAd at 2 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL18A1	NM_001379500.1	c.3250-15G>A		splice_polypyrimidine_tract_variant, intron_variant		ENST00000651438.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL18A1	ENST00000651438.1	c.3250-15G>A		splice_polypyrimidine_tract_variant, intron_variant			NM_001379500.1

Frequencies

GnomAD3 genomes AF: 0.00223 AC: 339 AN: 152122 Hom.: 2 Cov.: 33

Gnomad AFR AF: 0.000507

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00301

Gnomad ASJ AF: 0.0305

Gnomad EAS AF: 0.000386

Gnomad SAS AF: 0.00414

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.0253

Gnomad NFE AF: 0.00187

Gnomad OTH AF: 0.00382

GnomAD3 exomes AF: 0.00368 AC: 528 AN: 143294 Hom.: 5 AF XY: 0.00391 AC XY: 306 AN XY: 78348

Gnomad AFR exome AF: 0.000290

Gnomad AMR exome AF: 0.00177

Gnomad ASJ exome AF: 0.0288

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00384

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00229

Gnomad OTH exome AF: 0.00715

GnomAD4 exome AF: 0.00196 AC: 2733 AN: 1391312 Hom.: 18 Cov.: 32 AF XY: 0.00210 AC XY: 1440 AN XY: 686970

Gnomad4 AFR exome AF: 0.000570

Gnomad4 AMR exome AF: 0.00213

Gnomad4 ASJ exome AF: 0.0288

Gnomad4 EAS exome AF: 0.0000558

Gnomad4 SAS exome AF: 0.00407

Gnomad4 FIN exome AF: 0.0000238

Gnomad4 NFE exome AF: 0.00119

Gnomad4 OTH exome AF: 0.00419

GnomAD4 genome AF: 0.00223 AC: 339 AN: 152240 Hom.: 2 Cov.: 33 AF XY: 0.00220 AC XY: 164 AN XY: 74438

Gnomad4 AFR AF: 0.000506

Gnomad4 AMR AF: 0.00301

Gnomad4 ASJ AF: 0.0305

Gnomad4 EAS AF: 0.000386

Gnomad4 SAS AF: 0.00414

Gnomad4 FIN AF: 0.0000941

Gnomad4 NFE AF: 0.00187

Gnomad4 OTH AF: 0.00378

Alfa AF: 0.00527 Hom.: 1

Bravo AF: 0.00251

Asia WGS AF: 0.00202 AC: 7 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 19, 2024	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
Cadd	Benign	1.4
Dann	Benign	0.63
RBP_binding_hub_radar		0.91
RBP_regulation_power_radar		2.2

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: rs377715562; hg19: chr21-46929255;