rs145431028

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 2P and 8B. PP3_ModerateBS1BS2

The NM_033409.4(SLC52A3):c.1371C>G(p.Phe457Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000671 in 1,610,086 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.00045 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00069 ( 3 hom. )

Consequence

SLC52A3
NM_033409.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:8O:2

Conservation

PhyloP100: 2.78

Publications

11 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: ClinGen, Ambry Genetics, PanelApp Australia, Genomics England PanelApp, G2P, Labcorp Genetics (formerly Invitae)
progressive bulbar palsy
Inheritance: AR Classification: MODERATE Submitted by: Ambry Genetics

SLC52A3 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -6 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.858

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000453 (69/152358) while in subpopulation NFE AF = 0.000882 (60/68032). AF 95% confidence interval is 0.000703. There are 0 homozygotes in GnomAd4. There are 31 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 3 AR gene

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SLC52A3	NM_033409.4	MANE Select	c.1371C>G	p.Phe457Leu	missense	Exon 5 of 5	NP_212134.3
SLC52A3	NM_001370085.1		c.1371C>G	p.Phe457Leu	missense	Exon 6 of 6	NP_001357014.1	Q9NQ40-1
SLC52A3	NM_001370086.1		c.1371C>G	p.Phe457Leu	missense	Exon 6 of 6	NP_001357015.1	Q9NQ40-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SLC52A3	ENST00000645534.1	MANE Select	c.1371C>G	p.Phe457Leu	missense	Exon 5 of 5	ENSP00000494193.1	Q9NQ40-1
SLC52A3	ENST00000217254.11	TSL:5	c.1371C>G	p.Phe457Leu	missense	Exon 6 of 6	ENSP00000217254.7	Q9NQ40-1
SLC52A3	ENST00000488495.3	TSL:3	c.1371C>G	p.Phe457Leu	missense	Exon 5 of 5	ENSP00000494009.1	Q9NQ40-1

Frequencies

GnomAD3 genomes

AF:

0.000453

AC:

AN:

152240

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000965

Gnomad AMI

AF:

0.00220

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000882

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000374

AC:

AN:

237784

AF XY:

0.000353

show subpopulations

Gnomad AFR exome

AF:

0.0000709

Gnomad AMR exome

AF:

0.0000589

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000492

Gnomad NFE exome

AF:

0.000789

Gnomad OTH exome

AF:

0.000171

GnomAD4 exome

AF:

0.000694

AC:

1011

AN:

1457728

Hom.:

Cov.:

AF XY:

0.000639

AC XY:

463

AN XY:

724978

show subpopulations

African (AFR)

AF:

0.0000898

AC:

AN:

33394

American (AMR)

AF:

0.0000449

AC:

AN:

44500

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26094

East Asian (EAS)

AF:

0.00

AC:

AN:

39468

South Asian (SAS)

AF:

0.00

AC:

AN:

85692

European-Finnish (FIN)

AF:

0.0000964

AC:

AN:

51892

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5728

European-Non Finnish (NFE)

AF:

0.000872

AC:

969

AN:

1110768

Other (OTH)

AF:

0.000532

AC:

AN:

60192

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.485

Heterozygous variant carriers

123

184

246

307

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

114

152

190

<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

AF:

0.000453

AC:

AN:

152358

Hom.:

Cov.:

AF XY:

0.000416

AC XY:

AN XY:

74496

show subpopulations

African (AFR)

AF:

0.0000962

AC:

AN:

41588

American (AMR)

AF:

0.000131

AC:

AN:

15310

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5184

South Asian (SAS)

AF:

0.000207

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000882

AC:

AN:

68032

Other (OTH)

AF:

0.00

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome 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

Alfa

AF:

0.000672

Hom.:

Bravo

AF:

0.000427

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.00104

AC:

ESP6500AA

AF:

0.000231

AC:

ESP6500EA

AF:

0.000710

AC:

ExAC

AF:

0.000290

AC:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

Brown-Vialetto-van Laere syndrome 1 (4)

Inborn genetic diseases (1)

not specified (1)

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

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.97

BayesDel_addAF

Uncertain

0.095

BayesDel_noAF

Pathogenic

0.28

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.28

Eigen

Uncertain

0.26

Eigen_PC

Benign

0.074

FATHMM_MKL

Uncertain

0.91

LIST_S2

Benign

0.77

M_CAP

Uncertain

0.16

MetaRNN

Pathogenic

0.86

MetaSVM

Uncertain

0.20

MutationAssessor

Pathogenic

3.3

PhyloP100

2.8

PrimateAI

Uncertain

0.70

PROVEAN

Pathogenic

-5.5

REVEL

Pathogenic

0.78

Sift

Pathogenic

0.0

Sift4G

Uncertain

0.012

Polyphen

1.0

Vest4

0.97

MutPred

0.95

Gain of helix (P = 0.0696)

MVP

0.80

MPC

1.1

ClinPred

0.76

GERP RS

1.9

Varity_R

0.86

gMVP

0.82

Mutation Taster

=8/92

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over