NM_033409.4:c.1359G>A

Variant names:

• chr20-761077-C-T
• rs536993223
• NM_033409.4:c.1359G>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Moderate BP6_Moderate

The NM_033409.4(SLC52A3):​c.1359G>A​(p.Val453Val) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000186 in 1,609,934 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: SLC52A3 NM_033409.4 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.672
• 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: 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.41).
• BP6: Variant 20-761077-C-T is Benign according to our data. Variant chr20-761077-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 1087198.Status of the report is criteria_provided_single_submitter, 1 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.1359G>A	p.Val453Val	synonymous	Exon 5 of 5	NP_212134.3
	SLC52A3	NM_001370085.1		c.1359G>A	p.Val453Val	synonymous	Exon 6 of 6	NP_001357014.1	Q9NQ40-1
	SLC52A3	NM_001370086.1		c.1359G>A	p.Val453Val	synonymous	Exon 6 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.1359G>A	p.Val453Val	synonymous	Exon 5 of 5	ENSP00000494193.1	Q9NQ40-1
	SLC52A3	ENST00000473664.2	TSL:5	c.853G>A	p.Ala285Thr	missense	Exon 3 of 3	ENSP00000502741.1	A0A6Q8PHL7
	SLC52A3	ENST00000217254.11	TSL:5	c.1359G>A	p.Val453Val	synonymous	Exon 6 of 6	ENSP00000217254.7	Q9NQ40-1

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152228 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

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: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000843 AC: 2 AN: 237116 AF XY: 0.00000769

Gnomad AFR exome AF: 0.000141

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: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.86e-7 AC: 1 AN: 1457588 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 724876

⚠️ 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: 33392

American (AMR) AF: 0.00 AC: 0 AN: 44478

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26074

East Asian (EAS) AF: 0.00 AC: 0 AN: 39476

South Asian (SAS) AF: 0.00 AC: 0 AN: 85652

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51890

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5732

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1110706

Other (OTH) AF: 0.00 AC: 0 AN: 60188

⚠️ 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 AF: 0.0000131 AC: 2 AN: 152346 Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1 AN XY: 74492

African (AFR) AF: 0.0000240 AC: 1 AN: 41584

American (AMR) AF: 0.0000654 AC: 1 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68034

Other (OTH) AF: 0.00 AC: 0 AN: 2116

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.41
CADD	Benign	9.1
DANN	Benign	0.95
PhyloP100		0.67
Mutation Taster		=99/1	polymorphism

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: rs536993223; hg19: chr20-741721;