20-761057-G-A

Variant names:

• chr20-761057-G-A
• rs1227721934
• NM_033409.4:c.1379C>T

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM1 PM2

The NM_033409.4(SLC52A3):​c.1379C>T​(p.Ala460Val) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. A460A) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SLC52A3 NM_033409.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.58
• Publications: 0 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: Uncertain_significance. The variant received 4 ACMG points.

• PM1: In a disulfide_bond (size 77) in uniprot entity S52A3_HUMAN there are 5 pathogenic changes around while only 0 benign (100%) in NM_033409.4
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC52A3	NM_033409.4	c.1379C>T	p.Ala460Val	missense_variant	Exon 5 of 5	ENST00000645534.1	NP_212134.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC52A3	ENST00000645534.1	c.1379C>T	p.Ala460Val	missense_variant	Exon 5 of 5		NM_033409.4	ENSP00000494193.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Apr 02, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1379C>T (p.A460V) 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 1379, causing the alanine (A) at amino acid position 460 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Uncertain	0.072	D
BayesDel_noAF	Benign	-0.13
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.022	T;T;T;T
Eigen	Benign	0.17
Eigen_PC	Benign	0.053
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.92	.;.;.;D
M_CAP	Benign	0.067	D
MetaRNN	Uncertain	0.53	D;D;D;D
MetaSVM	Benign	-0.34	T
MutationAssessor	Uncertain	2.7	M;M;M;M
PhyloP100		5.6
PrimateAI	Uncertain	0.55	T
PROVEAN	Uncertain	-2.4	.;.;N;.
REVEL	Uncertain	0.31
Sift	Uncertain	0.018	.;.;D;.
Sift4G	Uncertain	0.013	.;D;D;.
Polyphen		1.0	D;D;D;D
Vest4		0.30, 0.30
MutPred		0.32		Loss of disorder (P = 0.0914);Loss of disorder (P = 0.0914);Loss of disorder (P = 0.0914);Loss of disorder (P = 0.0914);
MVP		0.78
MPC		0.73
ClinPred		0.95	D
GERP RS		4.4
Varity_R		0.15
gMVP		0.50
Mutation Taster		=63/37	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

Other links and lift over

dbSNP: rs1227721934; hg19: chr20-741701;