NM_033409.4:c.224T>C

Variant names:

• chr20-765551-A-G
• rs797045193
• NM_033409.4:c.224T>C

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_033409.4(SLC52A3):​c.224T>C​(p.Ile75Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000112 in 1,425,706 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 not provided (no stars).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.000011 (0 hom.)
• Consequence: SLC52A3 NM_033409.4 missense
• Clinical Significance: not provided no classification provided O:1
• Conservation: PhyloP100: 9.24
• Publications: 2 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: Ambry Genetics, G2P, ClinGen, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), PanelApp Australia
• progressive bulbar palsy

  Inheritance: AR Classification: MODERATE Submitted by: Ambry Genetics

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.794

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC52A3	NM_033409.4	MANE Select	c.224T>C	p.Ile75Thr	missense	Exon 2 of 5	NP_212134.3
	SLC52A3	NM_001370085.1		c.224T>C	p.Ile75Thr	missense	Exon 3 of 6	NP_001357014.1
	SLC52A3	NM_001370086.1		c.224T>C	p.Ile75Thr	missense	Exon 3 of 6	NP_001357015.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC52A3	ENST00000645534.1	MANE Select	c.224T>C	p.Ile75Thr	missense	Exon 2 of 5	ENSP00000494193.1
	SLC52A3	ENST00000217254.11	TSL:5	c.224T>C	p.Ile75Thr	missense	Exon 3 of 6	ENSP00000217254.7
	SLC52A3	ENST00000488495.3	TSL:3	c.224T>C	p.Ile75Thr	missense	Exon 2 of 5	ENSP00000494009.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD2 exomes AF: 0.00000523 AC: 1 AN: 191362 AF XY: 0.00000982

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000122

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000112 AC: 16 AN: 1425706 Hom.: 0 Cov.: 37 AF XY: 0.00000850 AC XY: 6 AN XY: 705562

African (AFR) AF: 0.00 AC: 0 AN: 32854

American (AMR) AF: 0.00 AC: 0 AN: 37848

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25372

East Asian (EAS) AF: 0.00 AC: 0 AN: 38132

South Asian (SAS) AF: 0.00 AC: 0 AN: 81648

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51182

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5722

European-Non Finnish (NFE) AF: 0.0000146 AC: 16 AN: 1093800

Other (OTH) AF: 0.00 AC: 0 AN: 59148

GnomAD4 genome Cov.: 31

ClinVar

Significance: not provided

Submissions summary: Other:1

Revision: no classification provided

Submissions by phenotype

Brown-Vialetto-van Laere syndrome 1 Other:1

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.45
BayesDel_addAF	Pathogenic	0.41	D
BayesDel_noAF	Pathogenic	0.35
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.24	T
Eigen	Pathogenic	0.85
Eigen_PC	Pathogenic	0.83
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.76	T
M_CAP	Uncertain	0.29	D
MetaRNN	Pathogenic	0.79	D
MetaSVM	Pathogenic	0.82	D
MutationAssessor	Uncertain	2.9	M
PhyloP100		9.2
PrimateAI	Uncertain	0.54	T
PROVEAN	Uncertain	-3.9	D
REVEL	Pathogenic	0.89
Sift	Uncertain	0.0040	D
Sift4G	Uncertain	0.019	D
Polyphen		0.99	D
Vest4		0.78
MutPred		0.55		Gain of glycosylation at I75 (P = 0.0158)
MVP		0.91
MPC		0.60
ClinPred		0.95	D
GERP RS		5.8
PromoterAI		-0.0061	Neutral
Varity_R		0.38
gMVP		0.90
Mutation Taster		=1/99	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs797045193; hg19: chr20-746195;