20-761055-C-A

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM1BP4BS1_Supporting

The NM_033409.4(SLC52A3):c.1381G>T(p.Asp461Tyr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000627 in 1,609,324 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.00026 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00067 ( 1 hom. )

Consequence

SLC52A3
NM_033409.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:6

Conservation

PhyloP100: 7.57

Publications

5 publications found

Variant links:

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]

SLC52A3 Gene-Disease associations (from GenCC):

Brown-Vialetto-van Laere syndrome 1
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, G2P, ClinGen, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), PanelApp Australia
progressive bulbar palsy
Inheritance: AR Classification: MODERATE Submitted by: Ambry Genetics

SLC52A3 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM1

In a disulfide_bond (size 77) in uniprot entity S52A3_HUMAN there are 5 pathogenic changes around while only 0 benign (100%) in NM_033409.4

BP4

Computational evidence support a benign effect (MetaRNN=0.41259673).

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000256 (39/152354) while in subpopulation NFE AF = 0.000514 (35/68034). AF 95% confidence interval is 0.000379. There are 0 homozygotes in GnomAd4. There are 16 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC52A3	NM_033409.4 link	c.1381G>T	p.Asp461Tyr	missense_variant	Exon 5 of 5	ENST00000645534.1	NP_212134.3	Q9NQ40-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC52A3	ENST00000645534.1 link	c.1381G>T	p.Asp461Tyr	missense_variant	Exon 5 of 5		NM_033409.4	ENSP00000494193.1		Q9NQ40-1

Frequencies

GnomAD3 genomes

AF:

0.000256

AC:

AN:

152236

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000724

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000941

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000514

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000377

AC:

AN:

236074

AF XY:

0.000362

show subpopulations

Gnomad AFR exome

AF:

0.0000727

Gnomad AMR exome

AF:

0.0000295

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000296

Gnomad NFE exome

AF:

0.000758

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000666

AC:

970

AN:

1456970

Hom.:

Cov.:

AF XY:

0.000646

AC XY:

468

AN XY:

724526

show subpopulations

African (AFR)

AF:

0.000120

AC:

AN:

33342

American (AMR)

AF:

0.00

AC:

AN:

44420

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26076

East Asian (EAS)

AF:

0.00

AC:

AN:

39390

South Asian (SAS)

AF:

0.00

AC:

AN:

85576

European-Finnish (FIN)

AF:

0.000309

AC:

AN:

51804

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5712

European-Non Finnish (NFE)

AF:

0.000838

AC:

931

AN:

1110480

Other (OTH)

AF:

0.000316

AC:

AN:

60170

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.488

Heterozygous variant carriers

121

181

242

302

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.000256

AC:

AN:

152354

Hom.:

Cov.:

AF XY:

0.000215

AC XY:

AN XY:

74498

show subpopulations

African (AFR)

AF:

0.0000722

AC:

AN:

41580

American (AMR)

AF:

0.00

AC:

AN:

15310

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5184

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.0000941

AC:

AN:

10628

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000514

AC:

AN:

68034

Other (OTH)

AF:

0.00

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.511

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.000588

Hom.:

Bravo

AF:

0.000306

TwinsUK

AF:

0.00135

AC:

ALSPAC

AF:

0.000778

AC:

ESP6500AA

AF:

0.000705

AC:

ESP6500EA

AF:

0.000240

AC:

ExAC

AF:

0.000374

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:3

Aug 01, 2018

CeGaT Center for Human Genetics Tuebingen

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 06, 2025

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Identified in two patients in the published literature with a second SLC52A3 variant with gait disturbance, muscle weakness, and hearing loss who both demonstrated improvement upon use of riboflavin therapy (PMID: 27777325, Marques et al., 2024); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 34662687, 27777325, 23506902, Marques2024[CaseReport], 33087424, 37845732, 38974615) -

Sep 25, 2024

Mayo Clinic Laboratories, Mayo Clinic

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Brown-Vialetto-van Laere syndrome 1

Uncertain:2

Jan 11, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces aspartic acid, which is acidic and polar, with tyrosine, which is neutral and polar, at codon 461 of the SLC52A3 protein (p.Asp461Tyr). This variant is present in population databases (rs140360713, gnomAD 0.07%). This missense change has been observed in individual(s) with clinical features of Brown-Vialetto-Van Laere syndrome (PMID: 27777325; Invitae). ClinVar contains an entry for this variant (Variation ID: 476604). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt SLC52A3 protein function with a negative predictive value of 80%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Jan 24, 2022

MGZ Medical Genetics Center

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Inborn genetic diseases

Uncertain:1

Dec 21, 2023

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.1381G>T (p.D461Y) alteration is located in exon 5 (coding exon 4) of the SLC52A3 gene. This alteration results from a G to T substitution at nucleotide position 1381, causing the aspartic acid (D) at amino acid position 461 to be replaced by a tyrosine (Y). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.33

BayesDel_addAF

Uncertain

0.051

BayesDel_noAF

Pathogenic

0.26

CADD

Uncertain

(source)

DANN

Benign

0.89

DEOGEN2

Benign

0.11

T;T;T;T

Eigen

Uncertain

0.39

Eigen_PC

Uncertain

0.39

FATHMM_MKL

Uncertain

0.97

LIST_S2

Benign

0.83

.;.;.;T

M_CAP

Benign

0.044

MetaRNN

Benign

0.41

T;T;T;T

MetaSVM

Benign

-0.31

MutationAssessor

Uncertain

2.5

M;M;M;M

PhyloP100

7.6

PrimateAI

Uncertain

0.62

PROVEAN

Pathogenic

-4.6

.;.;D;.

REVEL

Uncertain

0.53

Sift

Uncertain

0.0010

.;.;D;.

Sift4G

Uncertain

0.0060

.;D;D;.

Polyphen

0.93

P;P;P;P

Vest4

0.85, 0.85

MVP

0.76

MPC

0.94

ClinPred

0.54

GERP RS

5.3

Varity_R

0.72

gMVP

0.72

Mutation Taster

=39/61

disease causing

(source)

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

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20-761055-C-A

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over