rs3753019

Positions:

• chr21-45504871-C-T
• chr21-45504871-C-G
• chr21-45504871-C-A

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001379500.1(COL18A1):​c.2869-263C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.301 in 151,910 control chromosomes in the GnomAD database, including 7,180 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.30 (7180 hom., cov: 33)
• Consequence: COL18A1 NM_001379500.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.30

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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.442 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COL18A1	NM_001379500.1	c.2869-263C>T		intron_variant		ENST00000651438.1	NP_001366429.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COL18A1	ENST00000651438.1	c.2869-263C>T		intron_variant			NM_001379500.1	ENSP00000498485.1

Frequencies

GnomAD3 genomes AF: 0.302 AC: 45776 AN: 151792 Hom.: 7180 Cov.: 33

Gnomad AFR AF: 0.266

Gnomad AMI AF: 0.278

Gnomad AMR AF: 0.283

Gnomad ASJ AF: 0.293

Gnomad EAS AF: 0.457

Gnomad SAS AF: 0.446

Gnomad FIN AF: 0.248

Gnomad MID AF: 0.415

Gnomad NFE AF: 0.313

Gnomad OTH AF: 0.325

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.301 AC: 45778 AN: 151910 Hom.: 7180 Cov.: 33 AF XY: 0.303 AC XY: 22535 AN XY: 74256

Gnomad4 AFR AF: 0.266

Gnomad4 AMR AF: 0.282

Gnomad4 ASJ AF: 0.293

Gnomad4 EAS AF: 0.457

Gnomad4 SAS AF: 0.446

Gnomad4 FIN AF: 0.248

Gnomad4 NFE AF: 0.313

Gnomad4 OTH AF: 0.325

Alfa AF: 0.308 Hom.: 9578

Bravo AF: 0.299

Asia WGS AF: 0.421 AC: 1462 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.12
DANN	Benign	0.73

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs3753019; hg19: chr21-46924785;