rs797045195

Positions:

• chr20-763616-G-A

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_033409.4(SLC52A3):​c.955C>T​(p.Pro319Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000684 in 1,461,872 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000068 (0 hom.)
• Consequence: SLC52A3 NM_033409.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1 O:1
• Conservation: PhyloP100: 9.82

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 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.987

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SLC52A3	NM_033409.4	c.955C>T	p.Pro319Ser	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.955C>T	p.Pro319Ser	missense_variant	3/5		NM_033409.4	ENSP00000494193.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000684 AC: 10 AN: 1461872 Hom.: 0 Cov.: 32 AF XY: 0.00000825 AC XY: 6 AN XY: 727236

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000899

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1 Other:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 27, 2023

The c.955C>T (p.P319S) alteration is located in exon 3 (coding exon 2) of the SLC52A3 gene. This alteration results from a C to T substitution at nucleotide position 955, causing the proline (P) at amino acid position 319 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Brown-Vialetto-van Laere syndrome 1 Other:1

not provided, no classification provided

literature only

GeneReviews

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.30
BayesDel_addAF	Pathogenic	0.42	D
BayesDel_noAF	Pathogenic	0.37
CADD	Pathogenic	30
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.21	T;T;.;T;T
Eigen	Pathogenic	0.93
Eigen_PC	Pathogenic	0.86
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	.;.;D;.;D
M_CAP	Pathogenic	0.44	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D
MetaSVM	Uncertain	0.58	D
MutationAssessor	Pathogenic	3.5	H;H;H;H;H
PrimateAI	Uncertain	0.77	T
PROVEAN	Pathogenic	-7.3	.;.;D;D;.
REVEL	Pathogenic	0.86
Sift	Pathogenic	0.0	.;.;D;D;.
Sift4G	Uncertain	0.016	.;D;D;D;.
Polyphen		1.0	D;D;D;D;D
Vest4		0.57, 0.57
MutPred		0.92		Gain of helix (P = 0.0496);Gain of helix (P = 0.0496);Gain of helix (P = 0.0496);Gain of helix (P = 0.0496);Gain of helix (P = 0.0496);
MVP		0.86
MPC		1.0
ClinPred		1.0	D
GERP RS		5.1
Varity_R		0.74
gMVP		0.86

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs797045195; hg19: chr20-744260;