rs149622425

Positions:

chr20-765572-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_033409.4(SLC52A3):c.203G>C(p.Cys68Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000215 in 1,582,136 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.00014 ( 0 hom., cov: 31)

Exomes 𝑓: 0.00022 ( 0 hom. )

Consequence

SLC52A3
NM_033409.4 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.280

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 Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.12685952).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLC52A3	NM_033409.4 linkuse as main transcript	c.203G>C	p.Cys68Ser	missense_variant	2/5	ENST00000645534.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC52A3	ENST00000645534.1 linkuse as main transcript	c.203G>C	p.Cys68Ser	missense_variant	2/5		NM_033409.4	P1	Q9NQ40-1

Frequencies

GnomAD3 genomes

AF:

0.000145

AC:

AN:

152122

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000810

AC:

AN:

197594

Hom.:

AF XY:

0.0000855

AC XY:

AN XY:

105258

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 SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000572

Gnomad NFE exome

AF:

0.000163

Gnomad OTH exome

AF:

0.000196

GnomAD4 exome

AF:

0.000222

AC:

318

AN:

1430014

Hom.:

Cov.:

AF XY:

0.000225

AC XY:

159

AN XY:

708040

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000195

Gnomad4 NFE exome

AF:

0.000284

Gnomad4 OTH exome

AF:

0.000101

GnomAD4 genome

AF:

0.000145

AC:

AN:

152122

Hom.:

Cov.:

AF XY:

0.0000808

AC XY:

AN XY:

74290

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000655

Gnomad4 ASJ

AF:

0.000288

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000294

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000155

Hom.:

Bravo

AF:

0.0000907

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.0000331

AC:

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

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 01, 2022

The p.C68S variant (also known as c.203G>C), located in coding exon 1 of the SLC52A3 gene, results from a G to C substitution at nucleotide position 203. The cysteine at codon 68 is replaced by serine, an amino acid with dissimilar properties. This amino acid position is not well conserved in available 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

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Apr 26, 2021

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

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jan 15, 2024

This sequence change replaces cysteine, which is neutral and slightly polar, with serine, which is neutral and polar, at codon 68 of the SLC52A3 protein (p.Cys68Ser). This variant is present in population databases (rs149622425, gnomAD 0.02%). 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: 452583). 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.18

BayesDel_noAF

Benign

-0.23

CADD

Benign

DANN

Benign

0.82

DEOGEN2

Benign

0.0033

T;T;.;T;T

Eigen

Benign

-0.27

Eigen_PC

Benign

-0.10

FATHMM_MKL

Benign

0.76

M_CAP

Benign

0.018

MetaRNN

Benign

0.13

T;T;T;T;T

MetaSVM

Benign

-0.42

MutationAssessor

Benign

1.6

L;L;L;L;L

MutationTaster

Benign

0.84

D;D

PrimateAI

Benign

0.31

Polyphen

0.050

B;B;B;B;B

Vest4

0.10, 0.10

MutPred

0.39

Gain of disorder (P = 1e-04);Gain of disorder (P = 1e-04);Gain of disorder (P = 1e-04);Gain of disorder (P = 1e-04);Gain of disorder (P = 1e-04);

MVP

0.69

MPC

0.39

ClinPred

0.032

GERP RS

4.8

Varity_R

0.090

gMVP

0.46

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