21-45494349-T-C

Position:

• chr21-45494349-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000417954(SLC19A1):​c.*1986A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.127 in 657,348 control chromosomes in the GnomAD database, including 6,331 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.16 (2562 hom., cov: 33)
  • Exomes 𝑓: 0.12 (3769 hom.)
• Consequence: SLC19A1 ENST00000417954 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.802

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BP6: Variant 21-45494349-T-C is Benign according to our data. Variant chr21-45494349-T-C is described in ClinVar as [Benign]. Clinvar id is 1227858.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.296 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COL18A1	NM_001379500.1	c.2353-196T>C		intron_variant		ENST00000651438.1	NP_001366429.1
COL18A1	NM_130444.3	c.3598-196T>C		intron_variant			NP_569711.2
COL18A1	NM_030582.4	c.2893-196T>C		intron_variant			NP_085059.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COL18A1	ENST00000651438.1	c.2353-196T>C		intron_variant			NM_001379500.1	ENSP00000498485.1

Frequencies

GnomAD3 genomes AF: 0.159 AC: 23695 AN: 148560 Hom.: 2553 Cov.: 33

Gnomad AFR AF: 0.301

Gnomad AMI AF: 0.150

Gnomad AMR AF: 0.117

Gnomad ASJ AF: 0.167

Gnomad EAS AF: 0.222

Gnomad SAS AF: 0.0985

Gnomad FIN AF: 0.115

Gnomad MID AF: 0.142

Gnomad NFE AF: 0.0907

Gnomad OTH AF: 0.150

GnomAD4 exome AF: 0.117 AC: 59714 AN: 508658 Hom.: 3769 Cov.: 7 AF XY: 0.116 AC XY: 31431 AN XY: 271328

Gnomad4 AFR exome AF: 0.335

Gnomad4 AMR exome AF: 0.125

Gnomad4 ASJ exome AF: 0.164

Gnomad4 EAS exome AF: 0.215

Gnomad4 SAS exome AF: 0.0952

Gnomad4 FIN exome AF: 0.116

Gnomad4 NFE exome AF: 0.0979

Gnomad4 OTH exome AF: 0.146

GnomAD4 genome AF: 0.160 AC: 23743 AN: 148690 Hom.: 2562 Cov.: 33 AF XY: 0.160 AC XY: 11600 AN XY: 72538

Gnomad4 AFR AF: 0.301

Gnomad4 AMR AF: 0.116

Gnomad4 ASJ AF: 0.167

Gnomad4 EAS AF: 0.221

Gnomad4 SAS AF: 0.0989

Gnomad4 FIN AF: 0.115

Gnomad4 NFE AF: 0.0907

Gnomad4 OTH AF: 0.152

Alfa AF: 0.129 Hom.: 200

Bravo AF: 0.165

Asia WGS AF: 0.162 AC: 564 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 11, 2021	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	4.4
DANN	Benign	0.43

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: rs1556330; hg19: chr21-46914263;