NM_033409.4:c.1371C>G

Variant names:

• chr20-761065-G-C
• rs145431028
• NM_033409.4:c.1371C>G

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PP3_Moderate BS1_Supporting BS2

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
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:8 O:2
• Conservation: PhyloP100: 2.78
• Publications: 11 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: ClinGen, Ambry Genetics, PanelApp Australia, Genomics England PanelApp, G2P, Labcorp Genetics (formerly Invitae)
• progressive bulbar palsy

  Inheritance: AR Classification: MODERATE Submitted by: Ambry Genetics

ACMG classification

Our verdict: Likely_benign. The variant received -3 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. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• 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

Sel.	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

Sel.	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: 69 AN: 152240 Hom.: 0 Cov.: 32

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: 89 AN: 237784 AF XY: 0.000353

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.: 3 Cov.: 30 AF XY: 0.000639 AC XY: 463 AN XY: 724978

African (AFR) AF: 0.0000898 AC: 3 AN: 33394

American (AMR) AF: 0.0000449 AC: 2 AN: 44500

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26094

East Asian (EAS) AF: 0.00 AC: 0 AN: 39468

South Asian (SAS) AF: 0.00 AC: 0 AN: 85692

European-Finnish (FIN) AF: 0.0000964 AC: 5 AN: 51892

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5728

European-Non Finnish (NFE) AF: 0.000872 AC: 969 AN: 1110768

Other (OTH) AF: 0.000532 AC: 32 AN: 60192

GnomAD4 genome AF: 0.000453 AC: 69 AN: 152358 Hom.: 0 Cov.: 32 AF XY: 0.000416 AC XY: 31 AN XY: 74496

African (AFR) AF: 0.0000962 AC: 4 AN: 41588

American (AMR) AF: 0.000131 AC: 2 AN: 15310

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

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

European-Non Finnish (NFE) AF: 0.000882 AC: 60 AN: 68032

Other (OTH) AF: 0.00 AC: 0 AN: 2116

Alfa AF: 0.000672 Hom.: 0

Bravo AF: 0.000427

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.00104 AC: 4

ESP6500AA AF: 0.000231 AC: 1

ESP6500EA AF: 0.000710 AC: 6

ExAC AF: 0.000290 AC: 35

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	3	-	not provided (3)
-	2	-	Brown-Vialetto-van Laere syndrome 1 (4)
-	1	-	Inborn genetic diseases (1)
-	1	-	not specified (1)
-	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	D
BayesDel_noAF	Pathogenic	0.28
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.28	T
Eigen	Uncertain	0.26
Eigen_PC	Benign	0.074
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.77	T
M_CAP	Uncertain	0.16	D
MetaRNN	Pathogenic	0.86	D
MetaSVM	Uncertain	0.20	D
MutationAssessor	Pathogenic	3.3	M
PhyloP100		2.8
PrimateAI	Uncertain	0.70	T
PROVEAN	Pathogenic	-5.5	D
REVEL	Pathogenic	0.78
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.012	D
Polyphen		1.0	D
Vest4		0.97
MutPred		0.95		Gain of helix (P = 0.0696)
MVP		0.80
MPC		1.1
ClinPred		0.76	D
GERP RS		1.9
Varity_R		0.86
gMVP		0.82
Mutation Taster		=8/92	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: rs145431028; hg19: chr20-741709;