rs3746808

Positions:

• chr20-765454-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_033409.4(SLC52A3):​c.321C>T​(p.Ala107=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.303 in 1,609,184 control chromosomes in the GnomAD database, including 76,036 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.27 (6025 hom., cov: 31)
  • Exomes 𝑓: 0.31 (70011 hom.)
• Consequence: SLC52A3 NM_033409.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 2.24

Genes affected

SLC52A3 (HGNC:16187): (solute carrier family 52 member 3) This gene encodes a riboflavin transporter protein that is strongly expressed in the intestine and likely plays a role in intestinal absorption of riboflavin. The protein is predicted to have eleven transmembrane domains and a cell surface localization signal in the C-terminus. Mutations at this locus have been associated with Brown-Vialetto-Van Laere syndrome and Fazio-Londe disease. [provided by RefSeq, Mar 2012]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.52).
• BP6: Variant 20-765454-G-A is Benign according to our data. Variant chr20-765454-G-A is described in ClinVar as [Benign]. Clinvar id is 262233.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-765454-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=2.24 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.344 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SLC52A3	NM_033409.4	c.321C>T	p.Ala107=	synonymous_variant	2/5	ENST00000645534.1	NP_212134.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SLC52A3	ENST00000645534.1	c.321C>T	p.Ala107=	synonymous_variant	2/5		NM_033409.4	ENSP00000494193	P1

Frequencies

GnomAD3 genomes AF: 0.269 AC: 40879 AN: 151932 Hom.: 6014 Cov.: 31

Gnomad AFR AF: 0.161

Gnomad AMI AF: 0.210

Gnomad AMR AF: 0.314

Gnomad ASJ AF: 0.290

Gnomad EAS AF: 0.225

Gnomad SAS AF: 0.358

Gnomad FIN AF: 0.384

Gnomad MID AF: 0.291

Gnomad NFE AF: 0.304

Gnomad OTH AF: 0.263

GnomAD3 exomes AF: 0.321 AC: 77035 AN: 240208 Hom.: 12977 AF XY: 0.321 AC XY: 41744 AN XY: 129874

Gnomad AFR exome AF: 0.152

Gnomad AMR exome AF: 0.440

Gnomad ASJ exome AF: 0.291

Gnomad EAS exome AF: 0.217

Gnomad SAS exome AF: 0.372

Gnomad FIN exome AF: 0.378

Gnomad NFE exome AF: 0.304

Gnomad OTH exome AF: 0.305

GnomAD4 exome AF: 0.306 AC: 446195 AN: 1457132 Hom.: 70011 Cov.: 70 AF XY: 0.308 AC XY: 223093 AN XY: 724464

Gnomad4 AFR exome AF: 0.155

Gnomad4 AMR exome AF: 0.427

Gnomad4 ASJ exome AF: 0.298

Gnomad4 EAS exome AF: 0.219

Gnomad4 SAS exome AF: 0.372

Gnomad4 FIN exome AF: 0.372

Gnomad4 NFE exome AF: 0.302

Gnomad4 OTH exome AF: 0.290

GnomAD4 genome AF: 0.269 AC: 40909 AN: 152052 Hom.: 6025 Cov.: 31 AF XY: 0.274 AC XY: 20375 AN XY: 74282

Gnomad4 AFR AF: 0.161

Gnomad4 AMR AF: 0.315

Gnomad4 ASJ AF: 0.290

Gnomad4 EAS AF: 0.225

Gnomad4 SAS AF: 0.358

Gnomad4 FIN AF: 0.384

Gnomad4 NFE AF: 0.304

Gnomad4 OTH AF: 0.262

Alfa AF: 0.294 Hom.: 13742

Bravo AF: 0.260

Asia WGS AF: 0.317 AC: 1099 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Aug 23, 2017	p.Ala107Ala in exon 2 of SLC52A3: This variant is not expected to have clinical significance because it does not alter an amino acid residue, is not located wit hin the splice consensus sequence, and has been identified in 52.10% (4717/9054) of Latino chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.br oadinstitute.org; dbSNP rs3746808). -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 17, 2018	- -

Brown-Vialetto-van Laere syndrome 1 Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 14, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

Progressive bulbar palsy of childhood Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 14, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.52
CADD	Benign	6.6
DANN	Benign	0.37

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: rs3746808; hg19: chr20-746098; COSMIC: COSV54077309;