chr20-763738-G-A

Variant names:

• chr20-763738-G-A
• rs3746803
• NM_033409.4:c.833C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_033409.4(SLC52A3):​c.833C>T​(p.Thr278Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.106 in 1,614,094 control chromosomes in the GnomAD database, including 9,591 homozygotes. 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 Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T278R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.093 (700 hom., cov: 33)
  • Exomes 𝑓: 0.11 (8891 hom.)
• Consequence: SLC52A3 NM_033409.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 1.57
• Publications: 24 publications found

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

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0018212199).
• BP6: Variant 20-763738-G-A is Benign according to our data. Variant chr20-763738-G-A is described in ClinVar as Benign. ClinVar VariationId is 262240.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.124 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC52A3	NM_033409.4	c.833C>T	p.Thr278Met	missense_variant	Exon 3 of 5	ENST00000645534.1	NP_212134.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC52A3	ENST00000645534.1	c.833C>T	p.Thr278Met	missense_variant	Exon 3 of 5		NM_033409.4	ENSP00000494193.1

Frequencies

GnomAD3 genomes AF: 0.0931 AC: 14169 AN: 152174 Hom.: 699 Cov.: 33

Gnomad AFR AF: 0.0732

Gnomad AMI AF: 0.0186

Gnomad AMR AF: 0.0690

Gnomad ASJ AF: 0.122

Gnomad EAS AF: 0.0840

Gnomad SAS AF: 0.132

Gnomad FIN AF: 0.109

Gnomad MID AF: 0.0791

Gnomad NFE AF: 0.106

Gnomad OTH AF: 0.0866

GnomAD2 exomes AF: 0.101 AC: 25500 AN: 251306 AF XY: 0.105

Gnomad AFR exome AF: 0.0724

Gnomad AMR exome AF: 0.0603

Gnomad ASJ exome AF: 0.126

Gnomad EAS exome AF: 0.0757

Gnomad FIN exome AF: 0.113

Gnomad NFE exome AF: 0.108

Gnomad OTH exome AF: 0.101

GnomAD4 exome AF: 0.108 AC: 157634 AN: 1461802 Hom.: 8891 Cov.: 35 AF XY: 0.109 AC XY: 79009 AN XY: 727214

African (AFR) AF: 0.0662 AC: 2217 AN: 33480

American (AMR) AF: 0.0626 AC: 2800 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.128 AC: 3350 AN: 26136

East Asian (EAS) AF: 0.0809 AC: 3213 AN: 39696

South Asian (SAS) AF: 0.139 AC: 11988 AN: 86256

European-Finnish (FIN) AF: 0.113 AC: 6008 AN: 53404

Middle Eastern (MID) AF: 0.0794 AC: 458 AN: 5768

European-Non Finnish (NFE) AF: 0.109 AC: 121249 AN: 1111948

Other (OTH) AF: 0.105 AC: 6351 AN: 60392

GnomAD4 genome AF: 0.0931 AC: 14176 AN: 152292 Hom.: 700 Cov.: 33 AF XY: 0.0928 AC XY: 6908 AN XY: 74460

African (AFR) AF: 0.0732 AC: 3040 AN: 41556

American (AMR) AF: 0.0691 AC: 1057 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.122 AC: 424 AN: 3470

East Asian (EAS) AF: 0.0842 AC: 437 AN: 5190

South Asian (SAS) AF: 0.133 AC: 640 AN: 4826

European-Finnish (FIN) AF: 0.109 AC: 1157 AN: 10618

Middle Eastern (MID) AF: 0.0646 AC: 19 AN: 294

European-Non Finnish (NFE) AF: 0.106 AC: 7203 AN: 68010

Other (OTH) AF: 0.0862 AC: 182 AN: 2112

Alfa AF: 0.101 Hom.: 1734

Bravo AF: 0.0878

TwinsUK AF: 0.110 AC: 407

ALSPAC AF: 0.114 AC: 440

ESP6500AA AF: 0.0788 AC: 347

ESP6500EA AF: 0.110 AC: 943

ExAC AF: 0.104 AC: 12609

Asia WGS AF: 0.126 AC: 439 AN: 3478

EpiCase AF: 0.100

EpiControl AF: 0.0953

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 23, 2017

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

p.Thr278Met in exon 3 of SLC52A3: This variant is not expected to have clinical significance because it has been identified in 13.64% (2253/16512) of South Asia n chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstit ute.org; dbSNP rs3746803). -

not provided Benign:2

Aug 01, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 22471455) -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Progressive bulbar palsy of childhood;C0796274:Brown-Vialetto-van Laere syndrome 1 Benign:1

Mar 30, 2022

Fulgent Genetics, Fulgent Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Brown-Vialetto-van Laere syndrome 1 Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.066
BayesDel_addAF	Benign	-0.65	T
BayesDel_noAF	Benign	-0.59
CADD	Benign	11
DANN	Uncertain	0.98
DEOGEN2	Benign	0.0048	T;T;.;T;T
Eigen	Benign	-0.78
Eigen_PC	Benign	-0.84
FATHMM_MKL	Benign	0.15	N
LIST_S2	Benign	0.50	.;.;T;.;T
MetaRNN	Benign	0.0018	T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.55	N;N;N;N;N
PhyloP100		1.6
PrimateAI	Benign	0.24	T
PROVEAN	Benign	-0.29	.;.;N;N;.
REVEL	Benign	0.10
Sift	Benign	0.11	.;.;T;T;.
Sift4G	Benign	0.11	.;T;T;T;.
Polyphen		0.47	P;P;P;P;P
Vest4		0.016, 0.035
MPC		0.34
ClinPred		0.0038	T
GERP RS		2.4
Varity_R		0.019
gMVP		0.23
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs3746803; hg19: chr20-744382; COSMIC: COSV54076878;