Genetic Variant SLC52A3:p.Trp431Cys (chr20-761143-C-G) – ACMG Classification: Likely_pathogenic (6 pts)

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM1PM2PP3_Moderate

The NM_033409.4(SLC52A3):c.1293G>C(p.Trp431Cys) variant causes a missense change. The variant allele was found at a frequency of 0.000000695 in 1,438,406 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: 7.0e-7 ( 0 hom. )

Consequence

SLC52A3
NM_033409.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 4.63

Publications

1 publications found

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 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

SLC52A3 links:

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ACMG classification

Classification was made for transcript

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, 8 uncertain in NM_033409.4

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.911

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC52A3	NM_033409.4 link	c.1293G>C	p.Trp431Cys	missense_variant	Exon 5 of 5	ENST00000645534.1	NP_212134.3	Q9NQ40-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC52A3	ENST00000645534.1 link	c.1293G>C	p.Trp431Cys	missense_variant	Exon 5 of 5		NM_033409.4	ENSP00000494193.1		Q9NQ40-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000494

AC:

AN:

202574

AF XY:

0.00

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 FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000113

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

6.95e-7

AC:

AN:

1438406

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

713562

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32858

American (AMR)

AF:

0.00

AC:

AN:

41658

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25732

East Asian (EAS)

AF:

0.00

AC:

AN:

38124

South Asian (SAS)

AF:

0.00

AC:

AN:

82860

European-Finnish (FIN)

AF:

0.00

AC:

AN:

50362

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5488

European-Non Finnish (NFE)

AF:

9.08e-7

AC:

AN:

1101862

Other (OTH)

AF:

0.00

AC:

AN:

59462

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.44

BayesDel_addAF

Pathogenic

0.37

BayesDel_noAF

Pathogenic

0.30

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.36

T;T;T;T

Eigen

Pathogenic

0.82

Eigen_PC

Pathogenic

0.75

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.89

.;.;.;D

M_CAP

Uncertain

0.11

MetaRNN

Pathogenic

0.91

D;D;D;D

MetaSVM

Uncertain

0.37

MutationAssessor

Pathogenic

3.2

M;M;M;M

PhyloP100

4.6

PrimateAI

Uncertain

0.75

PROVEAN

Pathogenic

-11

.;.;D;.

REVEL

Uncertain

0.64

Sift

Uncertain

0.0020

.;.;D;.

Sift4G

Uncertain

0.0060

.;D;D;.

Polyphen

1.0

D;D;D;D

Vest4

0.48

MutPred

0.74

Loss of catalytic residue at L429 (P = 0.003);Loss of catalytic residue at L429 (P = 0.003);Loss of catalytic residue at L429 (P = 0.003);Loss of catalytic residue at L429 (P = 0.003);

MVP

0.85

MPC

0.88

ClinPred

1.0

GERP RS

5.2

Varity_R

0.87

gMVP

0.90

Mutation Taster

=5/95

disease causing

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over