rs527853872

Variant names:

• chr20-765372-T-C
• rs527853872
• NM_033409.4:c.403A>G

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Strong BS1

The NM_033409.4(SLC52A3):​c.403A>G​(p.Thr135Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000125 in 1,613,644 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.000079 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00013 (0 hom.)
• Consequence: SLC52A3 NM_033409.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: -1.02
• Publications: 3 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: ClinGen, Ambry Genetics, PanelApp Australia, Genomics England PanelApp, G2P, Labcorp Genetics (formerly Invitae)
• progressive bulbar palsy

  Inheritance: AR Classification: MODERATE Submitted by: Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.05620554).
• BS1: Variant frequency is greater than expected in population nfe. GnomAdExome4 allele frequency = 0.00013 (190/1461872) while in subpopulation NFE AF = 0.000161 (179/1112008). AF 95% confidence interval is 0.000141. There are 0 homozygotes in GnomAdExome4. There are 89 alleles in the male GnomAdExome4 subpopulation. Median coverage is 32. This position passed quality control check.

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.403A>G	p.Thr135Ala	missense	Exon 2 of 5	NP_212134.3
	SLC52A3	NM_001370085.1		c.403A>G	p.Thr135Ala	missense	Exon 3 of 6	NP_001357014.1	Q9NQ40-1
	SLC52A3	NM_001370086.1		c.403A>G	p.Thr135Ala	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.403A>G	p.Thr135Ala	missense	Exon 2 of 5	ENSP00000494193.1	Q9NQ40-1
	SLC52A3	ENST00000217254.11	TSL:5	c.403A>G	p.Thr135Ala	missense	Exon 3 of 6	ENSP00000217254.7	Q9NQ40-1
	SLC52A3	ENST00000488495.3	TSL:3	c.403A>G	p.Thr135Ala	missense	Exon 2 of 5	ENSP00000494009.1	Q9NQ40-1

Frequencies

GnomAD3 genomes AF: 0.0000791 AC: 12 AN: 151772 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000727

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000657

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000118

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000478 AC: 12 AN: 251292 AF XY: 0.0000368

Gnomad AFR exome AF: 0.0000616

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: 0.0000968

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000130 AC: 190 AN: 1461872 Hom.: 0 Cov.: 32 AF XY: 0.000122 AC XY: 89 AN XY: 727230

African (AFR) AF: 0.0000597 AC: 2 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53404

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.000161 AC: 179 AN: 1112008

Other (OTH) AF: 0.000132 AC: 8 AN: 60394

GnomAD4 genome AF: 0.0000791 AC: 12 AN: 151772 Hom.: 0 Cov.: 32 AF XY: 0.0000810 AC XY: 6 AN XY: 74100

African (AFR) AF: 0.0000727 AC: 3 AN: 41280

American (AMR) AF: 0.0000657 AC: 1 AN: 15232

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3460

East Asian (EAS) AF: 0.00 AC: 0 AN: 5168

South Asian (SAS) AF: 0.00 AC: 0 AN: 4786

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10574

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.000118 AC: 8 AN: 67966

Other (OTH) AF: 0.00 AC: 0 AN: 2082

Alfa AF: 0.0000965 Hom.: 0

Bravo AF: 0.0000642

ExAC AF: 0.0000412 AC: 5

EpiCase AF: 0.000218

EpiControl AF: 0.000119

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	Brown-Vialetto-van Laere syndrome 1 (1)
-	1	-	Inborn genetic diseases (1)
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.057
BayesDel_addAF	Benign	-0.38	T
BayesDel_noAF	Benign	-0.58
CADD	Benign	0.036
DANN	Benign	0.33
DEOGEN2	Benign	0.0042	T
Eigen	Benign	-1.8
Eigen_PC	Benign	-1.9
FATHMM_MKL	Benign	0.038	N
LIST_S2	Benign	0.69	T
M_CAP	Benign	0.016	T
MetaRNN	Benign	0.056	T
MetaSVM	Benign	-0.86	T
MutationAssessor	Benign	0.10	N
PhyloP100		-1.0
PrimateAI	Benign	0.32	T
PROVEAN	Benign	0.42	N
REVEL	Benign	0.13
Sift	Benign	0.44	T
Sift4G	Benign	0.59	T
Polyphen		0.0010	B
Vest4		0.022
MVP		0.24
MPC		0.31
ClinPred		0.046	T
GERP RS		-11
PromoterAI		0.030	Neutral
Varity_R		0.028
gMVP		0.34
Mutation Taster		=10/90	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

Other links and lift over

dbSNP: rs527853872; hg19: chr20-746016;