rs3746804

chr20-763771-G-A

Variant summary

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

The NM_033409.4(SLC52A3):c.800C>T(p.Pro267Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.211 in 1,614,056 control chromosomes in the GnomAD database, including 36,953 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. P267P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.19 (2817 hom., cov: 33)
  • Exomes 𝑓: 0.21 (34136 hom.)
• Consequence: SLC52A3 NM_033409.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.337

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0032471716).
• BP6: Variant 20-763771-G-A is Benign according to our data. Variant chr20-763771-G-A is described in ClinVar as [Benign]. Clinvar id is 262239.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-763771-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.257 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLC52A3	NM_033409.4	c.800C>T	p.Pro267Leu	missense_variant	3/5	ENST00000645534.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC52A3	ENST00000645534.1	c.800C>T	p.Pro267Leu	missense_variant	3/5		NM_033409.4	P1

Frequencies

GnomAD3 genomes AF: 0.187 AC: 28517 AN: 152138 Hom.: 2815 Cov.: 33

Gnomad AFR AF: 0.154

Gnomad AMI AF: 0.149

Gnomad AMR AF: 0.149

Gnomad ASJ AF: 0.173

Gnomad EAS AF: 0.269

Gnomad SAS AF: 0.183

Gnomad FIN AF: 0.207

Gnomad MID AF: 0.139

Gnomad NFE AF: 0.209

Gnomad OTH AF: 0.173

GnomAD3 exomes AF: 0.195 AC: 49004 AN: 251314 Hom.: 5155 AF XY: 0.197 AC XY: 26822 AN XY: 135834

Gnomad AFR exome AF: 0.151

Gnomad AMR exome AF: 0.113

Gnomad ASJ exome AF: 0.184

Gnomad EAS exome AF: 0.255

Gnomad SAS exome AF: 0.199

Gnomad FIN exome AF: 0.220

Gnomad NFE exome AF: 0.212

Gnomad OTH exome AF: 0.190

GnomAD4 exome AF: 0.213 AC: 311303 AN: 1461800 Hom.: 34136 Cov.: 68 AF XY: 0.213 AC XY: 154644 AN XY: 727204

Gnomad4 AFR exome AF: 0.143

Gnomad4 AMR exome AF: 0.117

Gnomad4 ASJ exome AF: 0.185

Gnomad4 EAS exome AF: 0.300

Gnomad4 SAS exome AF: 0.199

Gnomad4 FIN exome AF: 0.222

Gnomad4 NFE exome AF: 0.218

Gnomad4 OTH exome AF: 0.203

GnomAD4 genome AF: 0.188 AC: 28551 AN: 152256 Hom.: 2817 Cov.: 33 AF XY: 0.187 AC XY: 13891 AN XY: 74444

Gnomad4 AFR AF: 0.155

Gnomad4 AMR AF: 0.149

Gnomad4 ASJ AF: 0.173

Gnomad4 EAS AF: 0.269

Gnomad4 SAS AF: 0.183

Gnomad4 FIN AF: 0.207

Gnomad4 NFE AF: 0.209

Gnomad4 OTH AF: 0.171

Alfa AF: 0.202 Hom.: 6695

Bravo AF: 0.182

TwinsUK AF: 0.216 AC: 802

ALSPAC AF: 0.221 AC: 853

ESP6500AA AF: 0.162 AC: 713

ESP6500EA AF: 0.214 AC: 1837

ExAC AF: 0.198 AC: 24056

Asia WGS AF: 0.251 AC: 875 AN: 3478

EpiCase AF: 0.197

EpiControl AF: 0.193

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Aug 23, 2017	p.Pro267Leu in exon 3 of SLC52A3: This variant is not expected to have clinical significance because it has been identified in 26.27% (2264/8618) of East Asian chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitut e.org; dbSNP rs3746804). -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jul 08, 2018

- -

Brown-Vialetto-van Laere syndrome 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.073
BayesDel_addAF	Benign	-0.65	T
BayesDel_noAF	Benign	-0.56
Cadd	Benign	13
Dann	Benign	0.74
DEOGEN2	Benign	0.010	T;T;.;T;T
Eigen	Benign	-0.86
Eigen_PC	Benign	-0.83
FATHMM_MKL	Benign	0.11	N
MetaRNN	Benign	0.0032	T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.1	L;L;L;L;L
MutationTaster	Benign	1.0	P;P
PrimateAI	Benign	0.29	T
Polyphen		0.017	B;B;B;B;B
Vest4		0.018, 0.034
MPC		0.32
ClinPred		0.0018	T
GERP RS		0.14
Varity_R		0.037
gMVP		0.29

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: rs3746804; hg19: chr20-744415; COSMIC: COSV54076574;