rs3746802

chr20-763664-T-Cchr20-763664-T-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_033409.4(SLC52A3):c.907A>G(p.Ile303Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.107 in 1,614,092 control chromosomes in the GnomAD database, including 9,708 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I303L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.094 (711 hom., cov: 33)
  • Exomes 𝑓: 0.11 (8997 hom.)
• Consequence: SLC52A3 NM_033409.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 7.92

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0028273165).
• BP6: Variant 20-763664-T-C is Benign according to our data. Variant chr20-763664-T-C is described in ClinVar as [Benign]. Clinvar id is 262241.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-763664-T-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.127 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLC52A3	NM_033409.4	c.907A>G	p.Ile303Val	missense_variant	3/5	ENST00000645534.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC52A3	ENST00000645534.1	c.907A>G	p.Ile303Val	missense_variant	3/5		NM_033409.4	P1

Frequencies

GnomAD3 genomes AF: 0.0940 AC: 14294 AN: 152106 Hom.: 709 Cov.: 33

Gnomad AFR AF: 0.0734

Gnomad AMI AF: 0.0186

Gnomad AMR AF: 0.0696

Gnomad ASJ AF: 0.122

Gnomad EAS AF: 0.103

Gnomad SAS AF: 0.135

Gnomad FIN AF: 0.109

Gnomad MID AF: 0.0823

Gnomad NFE AF: 0.106

Gnomad OTH AF: 0.0880

GnomAD3 exomes AF: 0.103 AC: 25862 AN: 251384 Hom.: 1454 AF XY: 0.107 AC XY: 14515 AN XY: 135880

Gnomad AFR exome AF: 0.0724

Gnomad AMR exome AF: 0.0606

Gnomad ASJ exome AF: 0.126

Gnomad EAS exome AF: 0.0912

Gnomad SAS exome AF: 0.140

Gnomad FIN exome AF: 0.113

Gnomad NFE exome AF: 0.108

Gnomad OTH exome AF: 0.102

GnomAD4 exome AF: 0.109 AC: 158688 AN: 1461868 Hom.: 8997 Cov.: 35 AF XY: 0.109 AC XY: 79544 AN XY: 727234

Gnomad4 AFR exome AF: 0.0663

Gnomad4 AMR exome AF: 0.0628

Gnomad4 ASJ exome AF: 0.128

Gnomad4 EAS exome AF: 0.100

Gnomad4 SAS exome AF: 0.140

Gnomad4 FIN exome AF: 0.112

Gnomad4 NFE exome AF: 0.109

Gnomad4 OTH exome AF: 0.106

GnomAD4 genome AF: 0.0940 AC: 14306 AN: 152224 Hom.: 711 Cov.: 33 AF XY: 0.0938 AC XY: 6982 AN XY: 74416

Gnomad4 AFR AF: 0.0734

Gnomad4 AMR AF: 0.0696

Gnomad4 ASJ AF: 0.122

Gnomad4 EAS AF: 0.103

Gnomad4 SAS AF: 0.135

Gnomad4 FIN AF: 0.109

Gnomad4 NFE AF: 0.106

Gnomad4 OTH AF: 0.0900

Alfa AF: 0.103 Hom.: 2094

Bravo AF: 0.0886

TwinsUK AF: 0.110 AC: 408

ALSPAC AF: 0.114 AC: 441

ESP6500AA AF: 0.0788 AC: 347

ESP6500EA AF: 0.110 AC: 943

ExAC AF: 0.105 AC: 12782

Asia WGS AF: 0.151 AC: 525 AN: 3478

EpiCase AF: 0.100

EpiControl AF: 0.0954

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Aug 23, 2017	p.Ile303Val in exon 3 of SLC52A3: This variant is not expected to have clinical significance because it has been identified in 13.79% (2277/16510) of South Asia n chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstit ute.org; dbSNP rs3746802). -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Aug 01, 2018

This variant is associated with the following publications: (PMID: 22471455) -

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

Benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Mar 30, 2022

- -

Brown-Vialetto-van Laere syndrome 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.47	T
BayesDel_noAF	Benign	-0.33
Cadd	Benign	23
Dann	Uncertain	1.0
DEOGEN2	Benign	0.0082	T;T;.;T;T
Eigen	Pathogenic	0.68
Eigen_PC	Uncertain	0.61
FATHMM_MKL	Pathogenic	0.98	D
MetaRNN	Benign	0.0028	T;T;T;T;T
MetaSVM	Benign	-0.70	T
MutationAssessor	Pathogenic	3.2	M;M;M;M;M
MutationTaster	Benign	0.0000022	P;P
PrimateAI	Uncertain	0.49	T
Polyphen		1.0	D;D;D;D;D
Vest4		0.23, 0.28, 0.23
MPC		0.71
ClinPred		0.072	T
GERP RS		5.0
Varity_R		0.17
gMVP		0.31

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: rs3746802; hg19: chr20-744308; COSMIC: COSV54076870;