21-45495128-A-G

Position:

• chr21-45495128-A-G

Variant summary

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

The ENST00000417954.5(SLC19A1):​c.*1207T>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.273 in 641,592 control chromosomes in the GnomAD database, including 25,682 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 0.32 (8538 hom., cov: 34)
  • Exomes 𝑓: 0.26 (17144 hom.)
• Consequence: SLC19A1 ENST00000417954.5 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.700

Genes affected

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]

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]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.97).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.464 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL18A1	NM_001379500.1	c.2433+213A>G		intron_variant		ENST00000651438.1
COL18A1	NM_030582.4	c.2973+213A>G		intron_variant
COL18A1	NM_130444.3	c.3678+213A>G		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL18A1	ENST00000651438.1	c.2433+213A>G		intron_variant			NM_001379500.1

Frequencies

GnomAD3 genomes AF: 0.316 AC: 48047 AN: 152002 Hom.: 8514 Cov.: 34

Gnomad AFR AF: 0.469

Gnomad AMI AF: 0.287

Gnomad AMR AF: 0.242

Gnomad ASJ AF: 0.284

Gnomad EAS AF: 0.228

Gnomad SAS AF: 0.260

Gnomad FIN AF: 0.314

Gnomad MID AF: 0.316

Gnomad NFE AF: 0.253

Gnomad OTH AF: 0.294

GnomAD4 exome AF: 0.259 AC: 126766 AN: 489472 Hom.: 17144 Cov.: 5 AF XY: 0.260 AC XY: 67230 AN XY: 258438

Gnomad4 AFR exome AF: 0.479

Gnomad4 AMR exome AF: 0.212

Gnomad4 ASJ exome AF: 0.263

Gnomad4 EAS exome AF: 0.197

Gnomad4 SAS exome AF: 0.268

Gnomad4 FIN exome AF: 0.288

Gnomad4 NFE exome AF: 0.252

Gnomad4 OTH exome AF: 0.276

GnomAD4 genome AF: 0.316 AC: 48116 AN: 152120 Hom.: 8538 Cov.: 34 AF XY: 0.317 AC XY: 23574 AN XY: 74354

Gnomad4 AFR AF: 0.470

Gnomad4 AMR AF: 0.242

Gnomad4 ASJ AF: 0.284

Gnomad4 EAS AF: 0.228

Gnomad4 SAS AF: 0.262

Gnomad4 FIN AF: 0.314

Gnomad4 NFE AF: 0.253

Gnomad4 OTH AF: 0.294

Alfa AF: 0.251 Hom.: 6936

Bravo AF: 0.318

Asia WGS AF: 0.251 AC: 876 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.97
CADD	Benign	4.9
DANN	Benign	0.58

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: rs2236475; hg19: chr21-46915042; COSMIC: COSV60594768; COSMIC: COSV60594768;