rs145431028

Positions:

• chr20-761065-G-C

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 4P and 5B. PM1 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:7 O:2
• Conservation: PhyloP100: 2.78

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]

ACMG classification

Verdict is Likely_benign. Variant got -1 ACMG points.

• PM1: In a disulfide_bond (size 77) in uniprot entity S52A3_HUMAN there are 7 pathogenic changes around while only 1 benign (88%) in NM_033409.4
• 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 male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAdExome4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLC52A3	NM_033409.4	c.1371C>G	p.Phe457Leu	missense_variant	5/5	ENST00000645534.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC52A3	ENST00000645534.1	c.1371C>G	p.Phe457Leu	missense_variant	5/5		NM_033409.4	P1

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

GnomAD3 exomes AF: 0.000374 AC: 89 AN: 237784 Hom.: 0 AF XY: 0.000353 AC XY: 46 AN XY: 130456

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 SAS 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

Gnomad4 AFR exome AF: 0.0000898

Gnomad4 AMR exome AF: 0.0000449

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000964

Gnomad4 NFE exome AF: 0.000872

Gnomad4 OTH exome AF: 0.000532

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

Gnomad4 AFR AF: 0.0000962

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000882

Gnomad4 OTH AF: 0.00

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

Significance: Uncertain significance

Submissions summary: Uncertain:7 Other:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Brown-Vialetto-van Laere syndrome 1 Uncertain:2 Other:2

not provided, no classification provided	phenotyping only	GenomeConnect - Invitae Patient Insights Network	-	Variant interpreted as Uncertain significance and reported on 09-02-2020 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information. -
Uncertain significance, criteria provided, single submitter	clinical testing	Genetics and Molecular Pathology, SA Pathology	Jun 29, 2021	- -
not provided, no classification provided	literature only	GeneReviews	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Oct 26, 2022	This sequence change replaces phenylalanine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 457 of the SLC52A3 protein (p.Phe457Leu). This variant is present in population databases (rs145431028, gnomAD 0.08%). This missense change has been observed in individuals with Brown-Vialetto-Van Laere syndrome (BVVLS) (PMID: 20206331, 22740598, 28251916, 29053833). ClinVar contains an entry for this variant (Variation ID: 210029). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt SLC52A3 protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

not provided Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Dec 14, 2023	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 27777325, 20206331, 28251916, 22740598, 23107375, 31959559, 29053833, 26072523) -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	May 01, 2023	SLC52A3: PM2, PM3:Supporting, PP3 -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Aug 24, 2023

Variant summary: C20orf54 c.1371C>G (p.Phe457Leu) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00038 in 269176 control chromosomes (gnomAD). c.1371C>G has been reported in the literature in individuals affected with Brown-Vialetto Laere Syndrome without strong evidence of causality (Bansagi_2017, Green_2010, Johnson_2012, Manole_2017). These reports do not provide unequivocal conclusions about association of the variant with Brown-Vialetto Laere Syndrome 1. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 20206331, 22740598, 29053833, 28251916). Six submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. -

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 20, 2023

The c.1371C>G (p.F457L) alteration is located in exon 5 (coding exon 4) of the SLC52A3 gene. This alteration results from a C to G substitution at nucleotide position 1371, causing the phenylalanine (F) at amino acid position 457 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

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

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Jul 09, 2021

- -

Computational scores

Source: dbNSFP v4.3

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;T;T;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;D;D;D
MetaSVM	Uncertain	0.20	D
MutationAssessor	Pathogenic	3.3	M;M;M;M
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.70	T
PROVEAN	Pathogenic	-5.5	.;.;D;.
REVEL	Pathogenic	0.78
Sift	Pathogenic	0.0	.;.;D;.
Sift4G	Uncertain	0.012	.;D;D;.
Polyphen		1.0	D;D;D;D
Vest4		0.97, 0.97
MutPred		0.95		Gain of helix (P = 0.0696);Gain of helix (P = 0.0696);Gain of helix (P = 0.0696);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

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

LitVar

Other links and lift over

dbSNP: rs145431028; hg19: chr20-741709;