rs745750480

Variant names:

• chr20-761063-G-A
• rs745750480
• NM_033409.4:c.1373C>T

Your query was ambiguous. Multiple possible variants found:

• chr20-761063-G-A
• chr20-761063-G-T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 4P and 2B. PM1 PM2 BP4_Moderate

The NM_033409.4(SLC52A3):​c.1373C>T​(p.Ser458Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,457,490 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S458A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: SLC52A3 NM_033409.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.415
• 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 2 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
• BP4: Computational evidence support a benign effect (MetaRNN=0.1388466).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC52A3	NM_033409.4	c.1373C>T	p.Ser458Leu	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.1373C>T	p.Ser458Leu	missense_variant	Exon 5 of 5		NM_033409.4	ENSP00000494193.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1457490 Hom.: 0 Cov.: 30 AF XY: 0.00000276 AC XY: 2 AN XY: 724844

African (AFR) AF: 0.00 AC: 0 AN: 33390

American (AMR) AF: 0.00 AC: 0 AN: 44466

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26090

East Asian (EAS) AF: 0.00 AC: 0 AN: 39458

South Asian (SAS) AF: 0.00 AC: 0 AN: 85650

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51872

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5726

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1110662

Other (OTH) AF: 0.00 AC: 0 AN: 60176

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.090	T
BayesDel_noAF	Benign	-0.37
CADD	Benign	16
DANN	Benign	0.95
DEOGEN2	Benign	0.017	T;T;T;T
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.21	N
LIST_S2	Benign	0.65	.;.;.;T
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.14	T;T;T;T
MetaSVM	Benign	-0.92	T
MutationAssessor	Uncertain	2.3	M;M;M;M
PhyloP100		0.41
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-1.9	.;.;N;.
REVEL	Benign	0.13
Sift	Benign	0.17	.;.;T;.
Sift4G	Benign	0.24	.;T;T;.
Polyphen		0.55	P;P;P;P
Vest4		0.10, 0.10
MutPred		0.34		Loss of helix (P = 0.1299);Loss of helix (P = 0.1299);Loss of helix (P = 0.1299);Loss of helix (P = 0.1299);
MVP		0.37
MPC		0.29
ClinPred		0.14	T
GERP RS		-0.55
Varity_R		0.042
gMVP		0.13
Mutation Taster		=88/12	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: rs745750480; hg19: chr20-741707; COSMIC: COSV54079129;