20-765615-C-A

Variant names:

• chr20-765615-C-A
• rs797045191
• NM_033409.4:c.160G>T
• SLC52A3 p.Gly54Trp

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_033409.4(SLC52A3):​c.160G>T​(p.Gly54Trp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000069 in 1,449,016 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G54R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: SLC52A3 NM_033409.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.84
• Publications: 0 publications found

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]

SLC52A3 Gene-Disease associations (from GenCC):

• Brown-Vialetto-van Laere syndrome 1

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: PanelApp Australia, ClinGen, Genomics England PanelApp, Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae)
• progressive bulbar palsy

  Inheritance: AR Classification: MODERATE Submitted by: Ambry Genetics

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.983

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_033409.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC52A3	NM_033409.4	MANE Select	c.160G>T	p.Gly54Trp	missense	Exon 2 of 5	NP_212134.3
	SLC52A3	NM_001370085.1		c.160G>T	p.Gly54Trp	missense	Exon 3 of 6	NP_001357014.1	Q9NQ40-1
	SLC52A3	NM_001370086.1		c.160G>T	p.Gly54Trp	missense	Exon 3 of 6	NP_001357015.1	Q9NQ40-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC52A3	ENST00000645534.1	MANE Select	c.160G>T	p.Gly54Trp	missense	Exon 2 of 5	ENSP00000494193.1	Q9NQ40-1
	SLC52A3	ENST00000217254.11	TSL:5	c.160G>T	p.Gly54Trp	missense	Exon 3 of 6	ENSP00000217254.7	Q9NQ40-1
	SLC52A3	ENST00000488495.3	TSL:3	c.160G>T	p.Gly54Trp	missense	Exon 2 of 5	ENSP00000494009.1	Q9NQ40-1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 6.90e-7 AC: 1 AN: 1449016 Hom.: 0 Cov.: 36 AF XY: 0.00 AC XY: 0 AN XY: 719430

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0000299 AC: 1 AN: 33404

American (AMR) AF: 0.00 AC: 0 AN: 41952

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25686

East Asian (EAS) AF: 0.00 AC: 0 AN: 39210

South Asian (SAS) AF: 0.00 AC: 0 AN: 83704

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52550

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5756

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1106762

Other (OTH) AF: 0.00 AC: 0 AN: 59992

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.65
BayesDel_addAF	Pathogenic	0.36	D
BayesDel_noAF	Pathogenic	0.28
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.49	T
Eigen	Pathogenic	0.82
Eigen_PC	Pathogenic	0.73
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.97	D
M_CAP	Pathogenic	0.39	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Uncertain	0.61	D
MutationAssessor	Pathogenic	3.5	H
PhyloP100		7.8
PrimateAI	Uncertain	0.72	T
PROVEAN	Pathogenic	-7.9	D
REVEL	Pathogenic	0.81
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
PromoterAI		-0.017	Neutral
Varity_R		0.89
gMVP		0.96
Mutation Taster		=23/77	disease causing

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs797045191;

hg19: chr20-746259;