20-765380-C-T

Variant names:

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 4P and 5B. PM2PM5BP4_StrongBS1_Supporting

The NM_033409.4(SLC52A3):c.395G>A(p.Arg132Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000195 in 1,614,062 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R132W) has been classified as Pathogenic.

Frequency

Genomes: 𝑓 0.00021 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00019 ( 0 hom. )

Consequence

SLC52A3
NM_033409.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:1

Conservation

PhyloP100: -0.0150

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr20-765381-G-A is described in Lovd as [Pathogenic].

BP4

Computational evidence support a benign effect (MetaRNN=0.038506985).

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00021 (32/152202) while in subpopulation NFE AF= 0.000412 (28/68010). AF 95% confidence interval is 0.000293. There are 0 homozygotes in gnomad4. There are 15 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck. 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.395G>A	p.Arg132Gln	missense_variant	Exon 2 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.395G>A	p.Arg132Gln	missense_variant	Exon 2 of 5		NM_033409.4	ENSP00000494193.1		Q9NQ40-1

Frequencies

GnomAD3 genomes

AF:

0.000217

AC:

AN:

152084

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000966

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:

0.000426

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000139

AC:

AN:

251230

Hom.:

AF XY:

0.000140

AC XY:

AN XY:

135804

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000299

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000194

AC:

283

AN:

1461860

Hom.:

Cov.:

AF XY:

0.000193

AC XY:

140

AN XY:

727224

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000250

Gnomad4 OTH exome

AF:

0.0000662

GnomAD4 genome

AF:

0.000210

AC:

AN:

152202

Hom.:

Cov.:

AF XY:

0.000202

AC XY:

AN XY:

74402

show subpopulations

Gnomad4 AFR

AF:

0.0000963

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000412

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000338

Hom.:

Bravo

AF:

0.000204

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000778

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.000115

AC:

EpiCase

AF:

0.000491

EpiControl

AF:

0.000356

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Mar 23, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.R132Q variant (also known as c.395G>A), located in coding exon 1 of the SLC52A3 gene, results from a G to A substitution at nucleotide position 395. The arginine at codon 132 is replaced by glutamine, an amino acid with highly similar properties. This amino acid position is not well conserved in available vertebrate species, and glutamine is the reference amino acid in other vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

not provided

Uncertain:1

Jul 15, 2019

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; A different missense substitution at the same position (R132W) has been reported previously in association with Brown-Vialetto-Van Laere syndrome (Stenson et al., 2014); Has not been previously published as pathogenic or benign to our knowledge -

Brown-Vialetto-van Laere syndrome 1

Uncertain:1

Oct 29, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 132 of the SLC52A3 protein (p.Arg132Gln). This variant is present in population databases (rs142157418, gnomAD 0.03%). 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: 476610). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt SLC52A3 protein function with a negative predictive value of 95%. 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 specified

Benign:1

May 10, 2018

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

p.Arg132Gln in Exon 2 of SLC52A3: This variant is not expected to have clinical significance due to a lack of conservation across species, including mammals. Of note, more than 10 mammals have a Glutamine (Gln) at this position despite high nearby amino acid conservation. In addition, computational prediction tools do not suggest a high likelihood of impact to the protein. Additionally, this varia nt has been identified in 0.03% (38/126634) of European chromosomes by the Genom e Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs142157 418). ACMG/AMP Criteria applied: PM2, BP4_Strong -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.067

BayesDel_addAF

Benign

-0.35

BayesDel_noAF

Benign

-0.44

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.0087

T;T;.;T;T

Eigen

Benign

-0.60

Eigen_PC

Benign

-0.53

FATHMM_MKL

Benign

0.12

LIST_S2

Benign

0.77

.;.;T;.;T

M_CAP

Benign

0.029

MetaRNN

Benign

0.039

T;T;T;T;T

MetaSVM

Benign

-0.72

MutationAssessor

Benign

0.88

L;L;L;L;L

PrimateAI

Benign

0.24

PROVEAN

Benign

-1.3

.;.;N;N;.

REVEL

Benign

0.10

Sift

Benign

0.39

.;.;T;T;.

Sift4G

Benign

0.31

.;T;T;T;.

Polyphen

0.14

B;B;B;B;B

Vest4

0.069, 0.063

MVP

0.65

MPC

0.36

ClinPred

0.051

GERP RS

2.5

Varity_R

0.033

gMVP

0.35

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over