21-45493603-A-G

Position:

• chr21-45493603-A-G

Variant summary

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

The ENST00000417954.5(SLC19A1):​c.*2732T>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 0.433 in 1,526,298 control chromosomes in the GnomAD database, including 145,577 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.49 (19529 hom., cov: 35)
  • Exomes 𝑓: 0.43 (126048 hom.)
• Consequence: SLC19A1 ENST00000417954.5 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -2.28

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=-0.96).
• BP6: Variant 21-45493603-A-G is Benign according to our data. Variant chr21-45493603-A-G is described in ClinVar as [Benign]. Clinvar id is 261901.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr21-45493603-A-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.654 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COL18A1	NM_001379500.1	c.2352+28A>G		intron_variant		ENST00000651438.1	NP_001366429.1
COL18A1	NM_030582.4	c.2892+28A>G		intron_variant			NP_085059.2
COL18A1	NM_130444.3	c.3597+28A>G		intron_variant			NP_569711.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COL18A1	ENST00000651438.1	c.2352+28A>G		intron_variant			NM_001379500.1	ENSP00000498485

Frequencies

GnomAD3 genomes AF: 0.494 AC: 75028 AN: 152016 Hom.: 19502 Cov.: 35

Gnomad AFR AF: 0.660

Gnomad AMI AF: 0.380

Gnomad AMR AF: 0.437

Gnomad ASJ AF: 0.509

Gnomad EAS AF: 0.472

Gnomad SAS AF: 0.456

Gnomad FIN AF: 0.452

Gnomad MID AF: 0.462

Gnomad NFE AF: 0.416

Gnomad OTH AF: 0.489

GnomAD3 exomes AF: 0.444 AC: 66231 AN: 149326 Hom.: 15054 AF XY: 0.442 AC XY: 35353 AN XY: 79932

Gnomad AFR exome AF: 0.661

Gnomad AMR exome AF: 0.412

Gnomad ASJ exome AF: 0.493

Gnomad EAS exome AF: 0.482

Gnomad SAS exome AF: 0.445

Gnomad FIN exome AF: 0.432

Gnomad NFE exome AF: 0.417

Gnomad OTH exome AF: 0.445

GnomAD4 exome AF: 0.426 AC: 585308 AN: 1374162 Hom.: 126048 Cov.: 26 AF XY: 0.426 AC XY: 289499 AN XY: 679146

Gnomad4 AFR exome AF: 0.681

Gnomad4 AMR exome AF: 0.418

Gnomad4 ASJ exome AF: 0.500

Gnomad4 EAS exome AF: 0.458

Gnomad4 SAS exome AF: 0.447

Gnomad4 FIN exome AF: 0.418

Gnomad4 NFE exome AF: 0.413

Gnomad4 OTH exome AF: 0.447

GnomAD4 genome AF: 0.494 AC: 75100 AN: 152136 Hom.: 19529 Cov.: 35 AF XY: 0.495 AC XY: 36833 AN XY: 74374

Gnomad4 AFR AF: 0.661

Gnomad4 AMR AF: 0.436

Gnomad4 ASJ AF: 0.509

Gnomad4 EAS AF: 0.472

Gnomad4 SAS AF: 0.456

Gnomad4 FIN AF: 0.452

Gnomad4 NFE AF: 0.416

Gnomad4 OTH AF: 0.489

Alfa AF: 0.457 Hom.: 3008

Bravo AF: 0.502

Asia WGS AF: 0.466 AC: 1624 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

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 10, 2021	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.96
CADD	Benign	1.1
DANN	Benign	0.68

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: rs749627; hg19: chr21-46913517;