chr20-761166-G-A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_033409.4(SLC52A3):​c.1270C>T​(p.Leu424Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000342 in 1,577,484 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. L424L) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000059 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000032 ( 0 hom. )

Consequence

SLC52A3
NM_033409.4 missense

Scores

2
17

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:3

Conservation

PhyloP100: 1.79

Publications

0 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

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.068653196).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
SLC52A3NM_033409.4 linkc.1270C>T p.Leu424Phe 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
SLC52A3ENST00000645534.1 linkc.1270C>T p.Leu424Phe missense_variant Exon 5 of 5 NM_033409.4 ENSP00000494193.1 Q9NQ40-1

Frequencies

GnomAD3 genomes
AF:
0.0000591
AC:
9
AN:
152262
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000965
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:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000735
Gnomad OTH
AF:
0.00
GnomAD2 exomes
AF:
0.0000109
AC:
2
AN:
184004
AF XY:
0.0000100
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000257
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000316
AC:
45
AN:
1425222
Hom.:
0
Cov.:
30
AF XY:
0.0000340
AC XY:
24
AN XY:
705762
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
32494
American (AMR)
AF:
0.00
AC:
0
AN:
39576
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
25518
East Asian (EAS)
AF:
0.00
AC:
0
AN:
37372
South Asian (SAS)
AF:
0.00
AC:
0
AN:
81400
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
49424
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5200
European-Non Finnish (NFE)
AF:
0.0000374
AC:
41
AN:
1095298
Other (OTH)
AF:
0.0000679
AC:
4
AN:
58940
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.504
Heterozygous variant carriers
0
4
7
11
14
18
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Variant carriers
0
2
4
6
8
10
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
GnomAD4 genome
AF:
0.0000591
AC:
9
AN:
152262
Hom.:
0
Cov.:
32
AF XY:
0.0000538
AC XY:
4
AN XY:
74392
show subpopulations
African (AFR)
AF:
0.0000965
AC:
4
AN:
41470
American (AMR)
AF:
0.00
AC:
0
AN:
15292
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
3472
East Asian (EAS)
AF:
0.00
AC:
0
AN:
5198
South Asian (SAS)
AF:
0.00
AC:
0
AN:
4836
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
10630
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
316
European-Non Finnish (NFE)
AF:
0.0000735
AC:
5
AN:
68042
Other (OTH)
AF:
0.00
AC:
0
AN:
2094
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.531
Heterozygous variant carriers
0
1
2
3
4
5
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Genome Het
Variant carriers
0
2
4
6
8
10
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
Alfa
AF:
0.000214
Hom.:
0
Bravo
AF:
0.0000642
ESP6500AA
AF:
0.000231
AC:
1
ESP6500EA
AF:
0.00
AC:
0
ExAC
AF:
0.0000252
AC:
3

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Inborn genetic diseases Uncertain:1
Jun 07, 2025
Ambry Genetics
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

The c.1270C>T (p.L424F) alteration is located in exon 5 (coding exon 4) of the SLC52A3 gene. This alteration results from a C to T substitution at nucleotide position 1270, causing the leucine (L) at amino acid position 424 to be replaced by a phenylalanine (F). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided Uncertain:1
Jul 15, 2021
GeneDx
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

Not observed at significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Brown-Vialetto-van Laere syndrome 1 Uncertain:1
Jun 26, 2022
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This sequence change replaces leucine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 424 of the SLC52A3 protein (p.Leu424Phe). This variant is present in population databases (rs369230517, gnomAD 0.006%). This variant has not been reported in the literature in individuals affected with SLC52A3-related conditions. ClinVar contains an entry for this variant (Variation ID: 476599). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). 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. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.088
BayesDel_addAF
Benign
-0.21
T
BayesDel_noAF
Benign
-0.48
CADD
Uncertain
24
DANN
Uncertain
0.98
DEOGEN2
Benign
0.0038
T;T;T;T
Eigen
Benign
-0.57
Eigen_PC
Benign
-0.48
FATHMM_MKL
Uncertain
0.86
D
LIST_S2
Benign
0.85
.;.;.;D
M_CAP
Benign
0.041
D
MetaRNN
Benign
0.069
T;T;T;T
MetaSVM
Benign
-0.82
T
MutationAssessor
Benign
0.55
N;N;N;N
PhyloP100
1.8
PrimateAI
Benign
0.22
T
PROVEAN
Benign
-0.46
.;.;N;.
REVEL
Benign
0.071
Sift
Benign
0.10
.;.;T;.
Sift4G
Benign
0.071
.;T;T;.
Polyphen
0.042
B;B;B;B
Vest4
0.056
MVP
0.60
MPC
0.36
ClinPred
0.086
T
GERP RS
3.3
Varity_R
0.051
gMVP
0.15
Mutation Taster
=81/19
polymorphism

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

Other links and lift over

dbSNP: rs369230517; hg19: chr20-741810; API