rs6054614

Positions:

• chr20-765254-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_033409.4(SLC52A3):​c.521A>G​(p.Asp174Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00182 in 1,614,158 control chromosomes in the GnomAD database, including 29 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0096 (15 hom., cov: 32)
  • Exomes 𝑓: 0.0010 (14 hom.)
• Consequence: SLC52A3 NM_033409.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.418

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.003783226).
• BP6: Variant 20-765254-T-C is Benign according to our data. Variant chr20-765254-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 476611.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00964 (1468/152268) while in subpopulation AFR AF= 0.0333 (1383/41544). AF 95% confidence interval is 0.0318. There are 15 homozygotes in gnomad4. There are 684 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 15 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLC52A3	NM_033409.4	c.521A>G	p.Asp174Gly	missense_variant	2/5	ENST00000645534.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC52A3	ENST00000645534.1	c.521A>G	p.Asp174Gly	missense_variant	2/5		NM_033409.4	P1

Frequencies

GnomAD3 genomes AF: 0.00958 AC: 1458 AN: 152150 Hom.: 15 Cov.: 32

Gnomad AFR AF: 0.0331

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00341

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000415

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000176

Gnomad OTH AF: 0.00908

GnomAD3 exomes AF: 0.00271 AC: 682 AN: 251460 Hom.: 11 AF XY: 0.00198 AC XY: 269 AN XY: 135914

Gnomad AFR exome AF: 0.0372

Gnomad AMR exome AF: 0.00145

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000131

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000114

Gnomad OTH exome AF: 0.00163

GnomAD4 exome AF: 0.00101 AC: 1477 AN: 1461890 Hom.: 14 Cov.: 31 AF XY: 0.000884 AC XY: 643 AN XY: 727246

Gnomad4 AFR exome AF: 0.0356

Gnomad4 AMR exome AF: 0.00174

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000139

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000459

Gnomad4 OTH exome AF: 0.00214

GnomAD4 genome AF: 0.00964 AC: 1468 AN: 152268 Hom.: 15 Cov.: 32 AF XY: 0.00919 AC XY: 684 AN XY: 74448

Gnomad4 AFR AF: 0.0333

Gnomad4 AMR AF: 0.00340

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000415

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000176

Gnomad4 OTH AF: 0.00899

Alfa AF: 0.00186 Hom.: 5

Bravo AF: 0.0111

ESP6500AA AF: 0.0315 AC: 139

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.00340 AC: 413

Asia WGS AF: 0.00231 AC: 8 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.000178

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Sep 21, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 16, 2020	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Aug 23, 2017

p.Asp174Gly in exon 2 of SLC52A3: This variant is not expected to have clinical significance because it has been identified in 3.72% (386/10376) of African chro mosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.or g; dbSNP rs6054614). -

Brown-Vialetto-van Laere syndrome 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.064
BayesDel_addAF	Benign	-0.63	T
BayesDel_noAF	Benign	-0.64
CADD	Benign	2.0
DANN	Benign	0.69
DEOGEN2	Benign	0.0024	T;T;.;T;T
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.022	N
LIST_S2	Benign	0.44	.;.;T;.;T
MetaRNN	Benign	0.0038	T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.23	N;N;N;N;N
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-0.33	.;.;N;N;.
REVEL	Benign	0.077
Sift	Benign	0.53	.;.;T;T;.
Sift4G	Benign	0.57	.;T;T;T;.
Polyphen		0.0	B;B;B;B;B
Vest4		0.065, 0.070, 0.063
MVP		0.19
MPC		0.41
ClinPred		0.0020	T
GERP RS		-5.7
Varity_R		0.041
gMVP		0.37

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs6054614; hg19: chr20-745898;