chr20-763664-T-G

Position:

• chr20-763664-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_033409.4(SLC52A3):​c.907A>C​(p.Ile303Leu) 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 Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I303V) has been classified as Benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: SLC52A3 NM_033409.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• 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 Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.816

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SLC52A3	NM_033409.4	c.907A>C	p.Ile303Leu	missense_variant	3/5	ENST00000645534.1	NP_212134.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SLC52A3	ENST00000645534.1	c.907A>C	p.Ile303Leu	missense_variant	3/5		NM_033409.4	ENSP00000494193.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

May 07, 2023

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.094
BayesDel_addAF	Uncertain	0.012	T
BayesDel_noAF	Benign	-0.22
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.0036	T;T;.;T;T
Eigen	Uncertain	0.27
Eigen_PC	Uncertain	0.30
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.51	.;.;T;.;T
M_CAP	Benign	0.030	D
MetaRNN	Pathogenic	0.82	D;D;D;D;D
MetaSVM	Benign	-0.74	T
MutationAssessor	Benign	1.4	L;L;L;L;L
PrimateAI	Uncertain	0.55	T
PROVEAN	Benign	-0.93	.;.;N;N;.
REVEL	Uncertain	0.35
Sift	Benign	0.12	.;.;T;T;.
Sift4G	Benign	0.34	.;T;T;T;.
Polyphen		1.0	D;D;D;D;D
Vest4		0.65, 0.66
MutPred		0.54		Loss of catalytic residue at I303 (P = 0.1528);Loss of catalytic residue at I303 (P = 0.1528);Loss of catalytic residue at I303 (P = 0.1528);Loss of catalytic residue at I303 (P = 0.1528);Loss of catalytic residue at I303 (P = 0.1528);
MVP		0.79
MPC		0.39
ClinPred		0.90	D
GERP RS		5.0
Varity_R		0.25
gMVP		0.52

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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;