rs2838950

chr21-45506383-C-Tchr21-45506383-C-Gchr21-45506383-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.3216+417C>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 336,074 control chromosomes in the GnomAD database, including 17,242 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 0.31 (8198 hom., cov: 34)
  • Exomes 𝑓: 0.29 (9044 hom.)
• Consequence: COL18A1 NM_001379500.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.722

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=-0.96).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.544 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL18A1	NM_001379500.1	c.3216+417C>T		intron_variant		ENST00000651438.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL18A1	ENST00000651438.1	c.3216+417C>T		intron_variant			NM_001379500.1

Frequencies

GnomAD3 genomes AF: 0.313 AC: 47657 AN: 152072 Hom.: 8193 Cov.: 34

Gnomad AFR AF: 0.420

Gnomad AMI AF: 0.237

Gnomad AMR AF: 0.367

Gnomad ASJ AF: 0.288

Gnomad EAS AF: 0.561

Gnomad SAS AF: 0.429

Gnomad FIN AF: 0.196

Gnomad MID AF: 0.380

Gnomad NFE AF: 0.229

Gnomad OTH AF: 0.334

GnomAD4 exome AF: 0.292 AC: 53603 AN: 183884 Hom.: 9044 Cov.: 0 AF XY: 0.304 AC XY: 30367 AN XY: 99774

Gnomad4 AFR exome AF: 0.424

Gnomad4 AMR exome AF: 0.415

Gnomad4 ASJ exome AF: 0.269

Gnomad4 EAS exome AF: 0.575

Gnomad4 SAS exome AF: 0.402

Gnomad4 FIN exome AF: 0.206

Gnomad4 NFE exome AF: 0.222

Gnomad4 OTH exome AF: 0.285

GnomAD4 genome AF: 0.313 AC: 47684 AN: 152190 Hom.: 8198 Cov.: 34 AF XY: 0.316 AC XY: 23533 AN XY: 74400

Gnomad4 AFR AF: 0.420

Gnomad4 AMR AF: 0.367

Gnomad4 ASJ AF: 0.288

Gnomad4 EAS AF: 0.561

Gnomad4 SAS AF: 0.428

Gnomad4 FIN AF: 0.196

Gnomad4 NFE AF: 0.229

Gnomad4 OTH AF: 0.331

Alfa AF: 0.237 Hom.: 2525

Bravo AF: 0.332

Asia WGS AF: 0.482 AC: 1677 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.96
Cadd	Benign	0.65
Dann	Benign	0.60

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: rs2838950; hg19: chr21-46926297;