rs199588390

Variant names:

• chr20-765713-T-C
• rs199588390
• NM_033409.4:c.62A>G

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 4P and 1B. PM1 PP3 PP5 BS1_Supporting

The NM_033409.4(SLC52A3):​c.62A>G​(p.Asn21Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000126 in 1,613,538 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. N21N) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000059 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00013 (0 hom.)
• Consequence: SLC52A3 NM_033409.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:5 U:4 O:1
• Conservation: PhyloP100: 7.95
• Publications: 9 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 3 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, 5 uncertain in NM_033409.4
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.795
• PP5: Variant 20-765713-T-C is Pathogenic according to our data. Variant chr20-765713-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 210012.
• BS1: Variant frequency is greater than expected in population nfe. GnomAdExome4 allele frequency = 0.000133 (194/1461724) while in subpopulation NFE AF = 0.00015 (167/1111994). AF 95% confidence interval is 0.000132. There are 0 homozygotes in GnomAdExome4. There are 93 alleles in the male GnomAdExome4 subpopulation. Median coverage is 36. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

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.62A>G	p.Asn21Ser	missense	Exon 2 of 5	NP_212134.3
	SLC52A3	NM_001370085.1		c.62A>G	p.Asn21Ser	missense	Exon 3 of 6	NP_001357014.1
	SLC52A3	NM_001370086.1		c.62A>G	p.Asn21Ser	missense	Exon 3 of 6	NP_001357015.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC52A3	ENST00000645534.1	MANE Select	c.62A>G	p.Asn21Ser	missense	Exon 2 of 5	ENSP00000494193.1
	SLC52A3	ENST00000217254.11	TSL:5	c.62A>G	p.Asn21Ser	missense	Exon 3 of 6	ENSP00000217254.7
	SLC52A3	ENST00000488495.3	TSL:3	c.62A>G	p.Asn21Ser	missense	Exon 2 of 5	ENSP00000494009.1

Frequencies

GnomAD3 genomes AF: 0.0000593 AC: 9 AN: 151696 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000727

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000656

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000947

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.000480

GnomAD2 exomes AF: 0.000161 AC: 40 AN: 248370 AF XY: 0.000164

Gnomad AFR exome AF: 0.000186

Gnomad AMR exome AF: 0.0000290

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000218

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000225

Gnomad OTH exome AF: 0.000164

GnomAD4 exome AF: 0.000133 AC: 194 AN: 1461724 Hom.: 0 Cov.: 36 AF XY: 0.000128 AC XY: 93 AN XY: 727132

African (AFR) AF: 0.0000597 AC: 2 AN: 33480

American (AMR) AF: 0.0000224 AC: 1 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26114

East Asian (EAS) AF: 0.0000756 AC: 3 AN: 39700

South Asian (SAS) AF: 0.000128 AC: 11 AN: 86188

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53372

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.000150 AC: 167 AN: 1111994

Other (OTH) AF: 0.000166 AC: 10 AN: 60390

GnomAD4 genome AF: 0.0000593 AC: 9 AN: 151814 Hom.: 0 Cov.: 31 AF XY: 0.0000674 AC XY: 5 AN XY: 74184

African (AFR) AF: 0.0000725 AC: 3 AN: 41366

American (AMR) AF: 0.0000655 AC: 1 AN: 15258

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5130

South Asian (SAS) AF: 0.00 AC: 0 AN: 4778

European-Finnish (FIN) AF: 0.0000947 AC: 1 AN: 10556

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000442 AC: 3 AN: 67946

Other (OTH) AF: 0.000475 AC: 1 AN: 2104

Alfa AF: 0.0000975 Hom.: 0

Bravo AF: 0.000106

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.000189 AC: 23

EpiCase AF: 0.000164

EpiControl AF: 0.000237

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
2	1	-	not provided (3)
2	-	-	Brown-Vialetto-van Laere syndrome 1 (3)
-	2	-	not specified (2)
-	1	-	Inborn genetic diseases (1)
1	-	-	SLC52A3-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.084
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.17
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.34	T
Eigen	Pathogenic	0.84
Eigen_PC	Pathogenic	0.80
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.88	D
M_CAP	Uncertain	0.16	D
MetaRNN	Pathogenic	0.79	D
MetaSVM	Uncertain	0.39	D
MutationAssessor	Uncertain	2.9	M
PhyloP100		7.9
PrimateAI	Uncertain	0.53	T
PROVEAN	Pathogenic	-4.7	D
REVEL	Pathogenic	0.69
Sift	Uncertain	0.0080	D
Sift4G	Uncertain	0.018	D
Polyphen		1.0	D
Vest4		0.88
MVP		0.87
MPC		0.84
ClinPred		0.65	D
GERP RS		5.6
PromoterAI		-0.013	Neutral
Varity_R		0.34
gMVP		0.82
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

Other links and lift over

dbSNP: rs199588390; hg19: chr20-746357; COSMIC: COSV54076631;