rs1555783543

Positions:

• chr20-761742-A-G

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1 PM2 PP3_Strong PP5

The NM_033409.4(SLC52A3):​c.1156T>C​(p.Cys386Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency: Genomes: not found (cov: 33)
• Consequence: SLC52A3 NM_033409.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1
• Conservation: PhyloP100: 9.28

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_pathogenic. Variant got 9 ACMG points.

• PM1: In a mutagenesis_site Abolishes cell surface localization. (size 0) in uniprot entity S52A3_HUMAN
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.974
• PP5: Variant 20-761742-A-G is Pathogenic according to our data. Variant chr20-761742-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 521339.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SLC52A3	NM_033409.4	c.1156T>C	p.Cys386Arg	missense_variant	4/5	ENST00000645534.1	NP_212134.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SLC52A3	ENST00000645534.1	c.1156T>C	p.Cys386Arg	missense_variant	4/5		NM_033409.4	ENSP00000494193	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 33

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Inborn genetic diseases Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 20, 2017

- -

Brown-Vialetto-van Laere syndrome 1 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 04, 2020

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. 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 expected to disrupt SLC52A3 protein function. This variant has been observed in individual(s) with Brown-Vialetto-Van Laere syndrome (PMID: 28856173). ClinVar contains an entry for this variant (Variation ID: 521339). This variant is not present in population databases (ExAC no frequency). This sequence change replaces cysteine with arginine at codon 386 of the SLC52A3 protein (p.Cys386Arg). The cysteine residue is highly conserved and there is a large physicochemical difference between cysteine and arginine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.79
BayesDel_addAF	Pathogenic	0.37	D
BayesDel_noAF	Pathogenic	0.29
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Benign	0.14	T;T;.;T;T
Eigen	Pathogenic	0.70
Eigen_PC	Uncertain	0.64
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.90	.;.;D;.;D
M_CAP	Pathogenic	0.40	D
MetaRNN	Pathogenic	0.97	D;D;D;D;D
MetaSVM	Uncertain	0.096	D
MutationAssessor	Pathogenic	3.4	M;M;M;M;M
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.61	T
PROVEAN	Pathogenic	-7.8	.;.;D;D;.
REVEL	Pathogenic	0.73
Sift	Uncertain	0.0030	.;.;D;D;.
Sift4G	Uncertain	0.0060	.;D;D;D;.
Polyphen		1.0	D;D;D;D;D
Vest4		0.95, 0.90, 0.95
MutPred		0.85		Gain of disorder (P = 0.0396);Gain of disorder (P = 0.0396);Gain of disorder (P = 0.0396);Gain of disorder (P = 0.0396);Gain of disorder (P = 0.0396);
MVP		0.84
MPC		1.3
ClinPred		1.0	D
GERP RS		4.3
Varity_R		0.93
gMVP		0.83

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: rs1555783543; hg19: chr20-742386; COSMIC: COSV54077960;