20-765669-C-T
Position:
Variant summary
Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2PP3_StrongPP5
The NM_033409.4(SLC52A3):c.106G>A(p.Glu36Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000031 in 1,612,998 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.000013 ( 0 hom., cov: 31)
Exomes 𝑓: 0.000033 ( 0 hom. )
Consequence
SLC52A3
NM_033409.4 missense
NM_033409.4 missense
Scores
13
5
1
Clinical Significance
Conservation
PhyloP100: 7.79
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]
Genome browser will be placed here
ACMG classification
Classification made for transcript
Verdict is Likely_pathogenic. Variant got 7 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.969
PP5
Variant 20-765669-C-T is Pathogenic according to our data. Variant chr20-765669-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 143.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Pathogenic=1, Uncertain_significance=1, not_provided=1}. Variant chr20-765669-C-T is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
SLC52A3 | NM_033409.4 | c.106G>A | p.Glu36Lys | missense_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.106G>A | p.Glu36Lys | missense_variant | 2/5 | NM_033409.4 | ENSP00000494193 | P1 |
Frequencies
GnomAD3 genomes AF: 0.0000132 AC: 2AN: 151958Hom.: 0 Cov.: 31
GnomAD3 genomes
AF:
AC:
2
AN:
151958
Hom.:
Cov.:
31
Gnomad AFR
AF:
Gnomad AMI
AF:
Gnomad AMR
AF:
Gnomad ASJ
AF:
Gnomad EAS
AF:
Gnomad SAS
AF:
Gnomad FIN
AF:
Gnomad MID
AF:
Gnomad NFE
AF:
Gnomad OTH
AF:
GnomAD3 exomes AF: 0.0000162 AC: 4AN: 247354Hom.: 0 AF XY: 0.0000224 AC XY: 3AN XY: 133736
GnomAD3 exomes
AF:
AC:
4
AN:
247354
Hom.:
AF XY:
AC XY:
3
AN XY:
133736
Gnomad AFR exome
AF:
Gnomad AMR exome
AF:
Gnomad ASJ exome
AF:
Gnomad EAS exome
AF:
Gnomad SAS exome
AF:
Gnomad FIN exome
AF:
Gnomad NFE exome
AF:
Gnomad OTH exome
AF:
GnomAD4 exome AF: 0.0000329 AC: 48AN: 1461040Hom.: 0 Cov.: 37 AF XY: 0.0000427 AC XY: 31AN XY: 726696
GnomAD4 exome
AF:
AC:
48
AN:
1461040
Hom.:
Cov.:
37
AF XY:
AC XY:
31
AN XY:
726696
Gnomad4 AFR exome
AF:
Gnomad4 AMR exome
AF:
Gnomad4 ASJ exome
AF:
Gnomad4 EAS exome
AF:
Gnomad4 SAS exome
AF:
Gnomad4 FIN exome
AF:
Gnomad4 NFE exome
AF:
Gnomad4 OTH exome
AF:
GnomAD4 genome AF: 0.0000132 AC: 2AN: 151958Hom.: 0 Cov.: 31 AF XY: 0.0000135 AC XY: 1AN XY: 74204
GnomAD4 genome
AF:
AC:
2
AN:
151958
Hom.:
Cov.:
31
AF XY:
AC XY:
1
AN XY:
74204
Gnomad4 AFR
AF:
Gnomad4 AMR
AF:
Gnomad4 ASJ
AF:
Gnomad4 EAS
AF:
Gnomad4 SAS
AF:
Gnomad4 FIN
AF:
Gnomad4 NFE
AF:
Gnomad4 OTH
AF:
ExAC
AF:
AC:
3
EpiCase
AF:
EpiControl
AF:
ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:3Uncertain:1Other:1
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Brown-Vialetto-van Laere syndrome 1 Pathogenic:1Uncertain:1Other:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Mar 12, 2010 | - - |
not provided, no classification provided | literature only | GeneReviews | - | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Dec 21, 2023 | This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 36 of the SLC52A3 protein (p.Glu36Lys). This variant is present in population databases (rs267606686, gnomAD 0.003%). This missense change has been observed in individual(s) with Brown-Vialetto-Van Laere syndrome (BVVLS) (PMID: 20206331, 23688382, 29053833, 29950502). ClinVar contains an entry for this variant (Variation ID: 143). 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 expected to disrupt SLC52A3 protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects SLC52A3 function (PMID: 22273710). 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. - |
not provided Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Nov 09, 2021 | Identified in a patient with BVVLS who presented at 5 years old with sensorineural hearing loss, followed by speech difficulties, weakness, and respiratory issues; no second variant was identified (Malafronte et al., 2013); Published functional studies demonstrate reduced riboflavin uptake (Nabokina et al., 2012); Not observed at significant frequency in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 26072523, 22273710, 29950502, 23688382, 20206331, 23107375, 23506902, 29053833, 34662687) - |
Progressive bulbar palsy of childhood Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Mendelics | May 04, 2022 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Pathogenic
DEOGEN2
Uncertain
T;T;.;T;T
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Pathogenic
.;.;D;.;D
M_CAP
Uncertain
D
MetaRNN
Pathogenic
D;D;D;D;D
MetaSVM
Uncertain
D
MutationAssessor
Pathogenic
H;H;H;H;H
MutationTaster
Benign
D;D
PrimateAI
Uncertain
T
PROVEAN
Uncertain
.;.;D;D;.
REVEL
Pathogenic
Sift
Pathogenic
.;.;D;D;.
Sift4G
Pathogenic
.;D;D;D;.
Polyphen
D;D;D;D;D
Vest4
0.96, 0.96
MutPred
Gain of methylation at E36 (P = 0.0151);Gain of methylation at E36 (P = 0.0151);Gain of methylation at E36 (P = 0.0151);Gain of methylation at E36 (P = 0.0151);Gain of methylation at E36 (P = 0.0151);
MVP
0.86
MPC
1.1
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at