SLC52A3 p.Trp431Cys

Variant names:

• chr20-761143-C-A
• NM_033409.4:c.1293G>T
• SLC52A3 p.Trp431Cys

Your query was ambiguous. Multiple possible variants found:

• chr20-761143-C-A
• chr20-761143-C-G

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM1 PM2 PP3_Moderate

The NM_033409.4(SLC52A3):​c.1293G>T​(p.Trp431Cys) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: SLC52A3 NM_033409.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.63
• 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: PanelApp Australia, ClinGen, Genomics England PanelApp, Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae)
• progressive bulbar palsy

  Inheritance: AR Classification: MODERATE Submitted by: Ambry Genetics

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 9 uncertain in NM_033409.4
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.912

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_033409.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC52A3	NM_033409.4	MANE Select	c.1293G>T	p.Trp431Cys	missense	Exon 5 of 5	NP_212134.3
	SLC52A3	NM_001370085.1		c.1293G>T	p.Trp431Cys	missense	Exon 6 of 6	NP_001357014.1	Q9NQ40-1
	SLC52A3	NM_001370086.1		c.1293G>T	p.Trp431Cys	missense	Exon 6 of 6	NP_001357015.1	Q9NQ40-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC52A3	ENST00000645534.1	MANE Select	c.1293G>T	p.Trp431Cys	missense	Exon 5 of 5	ENSP00000494193.1	Q9NQ40-1
	SLC52A3	ENST00000217254.11	TSL:5	c.1293G>T	p.Trp431Cys	missense	Exon 6 of 6	ENSP00000217254.7	Q9NQ40-1
	SLC52A3	ENST00000488495.3	TSL:3	c.1293G>T	p.Trp431Cys	missense	Exon 5 of 5	ENSP00000494009.1	Q9NQ40-1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1438406 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 713562

African (AFR) AF: 0.00 AC: 0 AN: 32858

American (AMR) AF: 0.00 AC: 0 AN: 41658

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25732

East Asian (EAS) AF: 0.00 AC: 0 AN: 38124

South Asian (SAS) AF: 0.00 AC: 0 AN: 82860

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50362

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5488

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1101862

Other (OTH) AF: 0.00 AC: 0 AN: 59462

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.44
BayesDel_addAF	Pathogenic	0.37	D
BayesDel_noAF	Pathogenic	0.30
CADD	Pathogenic	33
DANN	Uncertain	0.99
DEOGEN2	Benign	0.36	T
Eigen	Pathogenic	0.82
Eigen_PC	Pathogenic	0.75
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.89	D
M_CAP	Uncertain	0.11	D
MetaRNN	Pathogenic	0.91	D
MetaSVM	Uncertain	0.37	D
MutationAssessor	Pathogenic	3.2	M
PhyloP100		4.6
PrimateAI	Uncertain	0.75	T
PROVEAN	Pathogenic	-11	D
REVEL	Uncertain	0.64
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0060	D
Varity_R		0.87
gMVP		0.90
Mutation Taster		=5/95	disease causing

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

hg19: chr20-741787;