chr20-765564-C-A

Variant names:

• chr20-765564-C-A
• rs267606683
• NM_033409.4:c.211G>T

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PVS1 PM2 PP5

The NM_033409.4(SLC52A3):​c.211G>T​(p.Glu71*) variant causes a stop gained change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000701 in 1,427,102 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 Pathogenic (no stars). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
• Consequence: SLC52A3 NM_033409.4 stop_gained
• Clinical Significance: Pathogenic no assertion criteria provided P:1 O:1
• Conservation: PhyloP100: 7.84
• Publications: 6 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: Pathogenic. The variant received 11 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 20-765564-C-A is Pathogenic according to our data. Variant chr20-765564-C-A is described in ClinVar as Pathogenic. ClinVar VariationId is 140.Status of the report is no_assertion_criteria_provided, 0 stars.

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.211G>T	p.Glu71*	stop_gained	Exon 2 of 5	NP_212134.3
	SLC52A3	NM_001370085.1		c.211G>T	p.Glu71*	stop_gained	Exon 3 of 6	NP_001357014.1	Q9NQ40-1
	SLC52A3	NM_001370086.1		c.211G>T	p.Glu71*	stop_gained	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.211G>T	p.Glu71*	stop_gained	Exon 2 of 5	ENSP00000494193.1	Q9NQ40-1
	SLC52A3	ENST00000217254.11	TSL:5	c.211G>T	p.Glu71*	stop_gained	Exon 3 of 6	ENSP00000217254.7	Q9NQ40-1
	SLC52A3	ENST00000488495.3	TSL:3	c.211G>T	p.Glu71*	stop_gained	Exon 2 of 5	ENSP00000494009.1	Q9NQ40-1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 7.01e-7 AC: 1 AN: 1427102 Hom.: 0 Cov.: 36 AF XY: 0.00000142 AC XY: 1 AN XY: 706294

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

African (AFR) AF: 0.00 AC: 0 AN: 32922

American (AMR) AF: 0.00 AC: 0 AN: 38088

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25370

East Asian (EAS) AF: 0.00 AC: 0 AN: 38184

South Asian (SAS) AF: 0.00 AC: 0 AN: 81688

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51230

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5726

European-Non Finnish (NFE) AF: 9.13e-7 AC: 1 AN: 1094708

Other (OTH) AF: 0.00 AC: 0 AN: 59186

⚠️ 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

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	Brown-Vialetto-van Laere syndrome 1 (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.66
CADD	Pathogenic	40
DANN	Uncertain	1.0
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.98
FATHMM_MKL	Pathogenic	0.99	D
PhyloP100		7.8
Vest4		0.87
GERP RS		5.8
PromoterAI		-0.024	Neutral
Mutation Taster		=1/199	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: rs267606683; hg19: chr20-746208;