Genetic Variant SLC52A3:p.Val81Met (chr20-765534-C-T) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_033409.4(SLC52A3):c.241G>A(p.Val81Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000357 in 1,575,926 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V81L) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00015 ( 0 hom., cov: 31)

Exomes 𝑓: 0.00038 ( 4 hom. )

Consequence

SLC52A3
NM_033409.4 missense

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: -0.905

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: 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: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.014178276).

BP6

Variant 20-765534-C-T is Benign according to our data. Variant chr20-765534-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 543066.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.000151 (23/152246) while in subpopulation SAS AF = 0.00436 (21/4822). AF 95% confidence interval is 0.00292. There are 0 homozygotes in GnomAd4. There are 16 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 4 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.241G>A	p.Val81Met	missense	Exon 2 of 5	NP_212134.3
SLC52A3	NM_001370085.1		c.241G>A	p.Val81Met	missense	Exon 3 of 6	NP_001357014.1	Q9NQ40-1
SLC52A3	NM_001370086.1		c.241G>A	p.Val81Met	missense	Exon 3 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.241G>A	p.Val81Met	missense	Exon 2 of 5	ENSP00000494193.1	Q9NQ40-1
SLC52A3	ENST00000217254.11	TSL:5	c.241G>A	p.Val81Met	missense	Exon 3 of 6	ENSP00000217254.7	Q9NQ40-1
SLC52A3	ENST00000488495.3	TSL:3	c.241G>A	p.Val81Met	missense	Exon 2 of 5	ENSP00000494009.1	Q9NQ40-1

Frequencies

GnomAD3 genomes

AF:

0.000158

AC:

AN:

152128

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00456

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000935

AC:

175

AN:

187138

AF XY:

0.00128

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:

0.0000377

Gnomad OTH exome

AF:

0.000201

GnomAD4 exome

AF:

0.000379

AC:

540

AN:

1423680

Hom.:

Cov.:

AF XY:

0.000549

AC XY:

387

AN XY:

704502

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32732

American (AMR)

AF:

0.00

AC:

AN:

37632

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25378

East Asian (EAS)

AF:

0.00

AC:

AN:

37806

South Asian (SAS)

AF:

0.00624

AC:

509

AN:

81606

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51126

Middle Eastern (MID)

AF:

0.000175

AC:

AN:

5720

European-Non Finnish (NFE)

AF:

0.00000732

AC:

AN:

1092590

Other (OTH)

AF:

0.000372

AC:

AN:

59090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.467

Heterozygous variant carriers

142

190

237

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

AF:

0.000151

AC:

AN:

152246

Hom.:

Cov.:

AF XY:

0.000215

AC XY:

AN XY:

74438

show subpopulations

African (AFR)

AF:

0.0000241

AC:

AN:

41550

American (AMR)

AF:

0.00

AC:

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5180

South Asian (SAS)

AF:

0.00436

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10614

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68010

Other (OTH)

AF:

0.00

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.490

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:

0.0000854

Hom.:

Bravo

AF:

0.0000453

ExAC

AF:

0.000839

AC:

101

Asia WGS

AF:

0.00202

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Brown-Vialetto-van Laere syndrome 1 (1)

Inborn genetic diseases (1)

SLC52A3-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.074

BayesDel_addAF

Benign

-0.45

BayesDel_noAF

Benign

-0.41

CADD

Benign

7.2

(source)

DANN

Benign

0.96

DEOGEN2

Benign

0.0078

Eigen

Benign

-0.78

Eigen_PC

Benign

-0.80

FATHMM_MKL

Benign

0.047

LIST_S2

Benign

0.65

M_CAP

Benign

0.084

MetaRNN

Benign

0.014

MetaSVM

Benign

-0.45

MutationAssessor

Uncertain

2.1

PhyloP100

-0.91

PrimateAI

Benign

0.33

PROVEAN

Benign

-1.1

REVEL

Benign

0.20

Sift

Benign

0.10

Sift4G

Benign

0.072

Polyphen

0.029

Vest4

0.11

MutPred

0.36

Loss of sheet (P = 0.0357)

MVP

0.62

MPC

0.33

ClinPred

0.030

GERP RS

1.5

PromoterAI

-0.011

Neutral

(source)

Varity_R

0.035

gMVP

0.34

Mutation Taster

=94/6

polymorphism

(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