21-45493600-G-A

Position:

• chr21-45493600-G-A

Variant summary

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

The ENST00000417954(SLC19A1):​c.*2735C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0156 in 1,525,146 control chromosomes in the GnomAD database, including 926 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.034 (222 hom., cov: 34)
  • Exomes 𝑓: 0.014 (704 hom.)
• Consequence: SLC19A1 ENST00000417954 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.422

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]

COL18A1 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.94).
• BP6: Variant 21-45493600-G-A is Benign according to our data. Variant chr21-45493600-G-A is described in ClinVar as [Benign]. Clinvar id is 1286364.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0892 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COL18A1	NM_001379500.1	c.2352+25G>A		intron_variant		ENST00000651438.1	NP_001366429.1
COL18A1	NM_130444.3	c.3597+25G>A		intron_variant			NP_569711.2
COL18A1	NM_030582.4	c.2892+25G>A		intron_variant			NP_085059.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COL18A1	ENST00000651438.1	c.2352+25G>A		intron_variant			NM_001379500.1	ENSP00000498485.1

Frequencies

GnomAD3 genomes AF: 0.0344 AC: 5234 AN: 152184 Hom.: 221 Cov.: 34

Gnomad AFR AF: 0.0915

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0167

Gnomad ASJ AF: 0.00634

Gnomad EAS AF: 0.0954

Gnomad SAS AF: 0.0573

Gnomad FIN AF: 0.00132

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.00473

Gnomad OTH AF: 0.0258

GnomAD3 exomes AF: 0.0221 AC: 3308 AN: 149486 Hom.: 116 AF XY: 0.0228 AC XY: 1825 AN XY: 80022

Gnomad AFR exome AF: 0.0958

Gnomad AMR exome AF: 0.00651

Gnomad ASJ exome AF: 0.00716

Gnomad EAS exome AF: 0.0886

Gnomad SAS exome AF: 0.0466

Gnomad FIN exome AF: 0.00165

Gnomad NFE exome AF: 0.00529

Gnomad OTH exome AF: 0.0142

GnomAD4 exome AF: 0.0135 AC: 18541 AN: 1372844 Hom.: 704 Cov.: 28 AF XY: 0.0140 AC XY: 9491 AN XY: 678590

Gnomad4 AFR exome AF: 0.101

Gnomad4 AMR exome AF: 0.00759

Gnomad4 ASJ exome AF: 0.00804

Gnomad4 EAS exome AF: 0.135

Gnomad4 SAS exome AF: 0.0448

Gnomad4 FIN exome AF: 0.00132

Gnomad4 NFE exome AF: 0.00509

Gnomad4 OTH exome AF: 0.0195

GnomAD4 genome AF: 0.0344 AC: 5244 AN: 152302 Hom.: 222 Cov.: 34 AF XY: 0.0350 AC XY: 2603 AN XY: 74472

Gnomad4 AFR AF: 0.0916

Gnomad4 AMR AF: 0.0167

Gnomad4 ASJ AF: 0.00634

Gnomad4 EAS AF: 0.0954

Gnomad4 SAS AF: 0.0567

Gnomad4 FIN AF: 0.00132

Gnomad4 NFE AF: 0.00473

Gnomad4 OTH AF: 0.0255

Alfa AF: 0.0172 Hom.: 18

Bravo AF: 0.0374

Asia WGS AF: 0.0680 AC: 237 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 14, 2021	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	0.31
DANN	Benign	0.77
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0

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: rs77010332; hg19: chr21-46913514;