20-763524-C-T

Variant names:

• chr20-763524-C-T
• rs147369439
• NM_033409.4:c.1047G>A

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_033409.4(SLC52A3):​c.1047G>A​(p.Ser349Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00136 in 1,614,036 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. S349S) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0012 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0014 (6 hom.)
• Consequence: SLC52A3 NM_033409.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 2.55
• Publications: 1 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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.36).
• BP6: Variant 20-763524-C-T is Benign according to our data. Variant chr20-763524-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 476598.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=2.55 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00124 (189/152296) while in subpopulation NFE AF = 0.00165 (112/68014). AF 95% confidence interval is 0.0014. There are 0 homozygotes in GnomAd4. There are 89 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 6 AR gene

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.1047G>A	p.Ser349Ser	synonymous	Exon 3 of 5	NP_212134.3
	SLC52A3	NM_001370085.1		c.1047G>A	p.Ser349Ser	synonymous	Exon 4 of 6	NP_001357014.1	Q9NQ40-1
	SLC52A3	NM_001370086.1		c.1047G>A	p.Ser349Ser	synonymous	Exon 4 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.1047G>A	p.Ser349Ser	synonymous	Exon 3 of 5	ENSP00000494193.1	Q9NQ40-1
	SLC52A3	ENST00000217254.11	TSL:5	c.1047G>A	p.Ser349Ser	synonymous	Exon 4 of 6	ENSP00000217254.7	Q9NQ40-1
	SLC52A3	ENST00000488495.3	TSL:3	c.1047G>A	p.Ser349Ser	synonymous	Exon 3 of 5	ENSP00000494009.1	Q9NQ40-1

Frequencies

GnomAD3 genomes AF: 0.00125 AC: 190 AN: 152178 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000338

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000589

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00124

Gnomad FIN AF: 0.00395

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00165

Gnomad OTH AF: 0.00239

GnomAD2 exomes AF: 0.00132 AC: 331 AN: 251288 AF XY: 0.00133

Gnomad AFR exome AF: 0.000369

Gnomad AMR exome AF: 0.000723

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00450

Gnomad NFE exome AF: 0.00142

Gnomad OTH exome AF: 0.00212

GnomAD4 exome AF: 0.00137 AC: 2005 AN: 1461740 Hom.: 6 Cov.: 32 AF XY: 0.00139 AC XY: 1011 AN XY: 727160

African (AFR) AF: 0.000329 AC: 11 AN: 33474

American (AMR) AF: 0.000693 AC: 31 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26132

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.000986 AC: 85 AN: 86250

European-Finnish (FIN) AF: 0.00613 AC: 327 AN: 53354

Middle Eastern (MID) AF: 0.000347 AC: 2 AN: 5768

European-Non Finnish (NFE) AF: 0.00131 AC: 1460 AN: 1111956

Other (OTH) AF: 0.00144 AC: 87 AN: 60386

GnomAD4 genome AF: 0.00124 AC: 189 AN: 152296 Hom.: 0 Cov.: 33 AF XY: 0.00120 AC XY: 89 AN XY: 74470

African (AFR) AF: 0.000337 AC: 14 AN: 41564

American (AMR) AF: 0.000523 AC: 8 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5180

South Asian (SAS) AF: 0.00124 AC: 6 AN: 4826

European-Finnish (FIN) AF: 0.00395 AC: 42 AN: 10624

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00165 AC: 112 AN: 68014

Other (OTH) AF: 0.00237 AC: 5 AN: 2112

Alfa AF: 0.000961 Hom.: 0

Bravo AF: 0.000759

EpiCase AF: 0.000927

EpiControl AF: 0.000711

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	2	not specified (2)
-	-	1	Brown-Vialetto-van Laere syndrome 1 (1)
-	-	1	Inborn genetic diseases (1)
-	-	1	SLC52A3-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.36
CADD	Benign	7.0
DANN	Benign	0.44
PhyloP100		2.5
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: rs147369439; hg19: chr20-744168; COSMIC: COSV99447705;