17-5033031-C-T

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_017986.4(SLC52A1):c.1273G>A(p.Ala425Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000514 in 1,613,630 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000053 (0 hom.)
• Consequence: SLC52A1 NM_017986.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.859

Genes affected

SLC52A1 (HGNC:30225): (solute carrier family 52 member 1) Biological redox reactions require electron donors and acceptor. Vitamin B2 is the source for the flavin in flavin adenine dinucleotide (FAD) and flavin mononucleotide (FMN) which are common redox reagents. This gene encodes a member of the riboflavin (vitamin B2) transporter family. Haploinsufficiency of this protein can cause maternal riboflavin deficiency. Multiple alternatively spliced variants, encoding the same protein, have been identified. [provided by RefSeq, Jan 2013]

LOC105371501 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.03276205).
• BS2: High AC in GnomAd at 5 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLC52A1	NM_017986.4	c.1273G>A	p.Ala425Thr	missense_variant	5/5	ENST00000254853.10
LOC105371501	XR_002958101.2	n.339+1362C>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC52A1	ENST00000254853.10	c.1273G>A	p.Ala425Thr	missense_variant	5/5	1	NM_017986.4	P1

Frequencies

GnomAD3 genomes AF: 0.0000329 AC: 5 AN: 152122 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.0000735

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000120 AC: 3 AN: 250108 Hom.: 0 AF XY: 0.0000148 AC XY: 2 AN XY: 135186

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000177

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.0000534 AC: 78 AN: 1461508 Hom.: 0 Cov.: 30 AF XY: 0.0000619 AC XY: 45 AN XY: 727042

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000189

Gnomad4 NFE exome AF: 0.0000665

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome AF: 0.0000329 AC: 5 AN: 152122 Hom.: 0 Cov.: 31 AF XY: 0.0000269 AC XY: 2 AN XY: 74288

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000735

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000789 Hom.: 0

Bravo AF: 0.0000264

ExAC AF: 0.0000165 AC: 2

EpiCase AF: 0.0000545

EpiControl AF: 0.000119

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Ariboflavinosis Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jul 05, 2022

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The threonine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. ClinVar contains an entry for this variant (Variation ID: 1352378). This variant has not been reported in the literature in individuals affected with SLC52A1-related conditions. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 425 of the SLC52A1 protein (p.Ala425Thr). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.078
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.59
Cadd	Benign	0.74
Dann	Benign	0.52
DEOGEN2	Benign	0.0057	T;T
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.010	N
M_CAP	Benign	0.0083	T
MetaRNN	Benign	0.033	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.62	N;N
MutationTaster	Benign	0.97	D;N;N
PrimateAI	Benign	0.35	T
PROVEAN	Benign	0.35	N;N
REVEL	Benign	0.071
Sift	Benign	0.49	T;T
Sift4G	Benign	0.56	T;T
Polyphen		0.0010	B;B
Vest4		0.097
MutPred		0.27		Gain of glycosylation at A425 (P = 0.0471);Gain of glycosylation at A425 (P = 0.0471);
MVP		0.072
MPC		0.084
ClinPred		0.031	T
GERP RS		-0.18
Varity_R		0.025
gMVP		0.13

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: rs747887020; hg19: chr17-4936326; COSMIC: COSV54693629; COSMIC: COSV54693629;