chr20-765553-G-C

Position:

• chr20-765553-G-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_033409.4(SLC52A3):​c.222C>G​(p.Ile74Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0882 in 1,577,444 control chromosomes in the GnomAD database, including 6,879 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.063 (390 hom., cov: 31)
  • Exomes 𝑓: 0.091 (6489 hom.)
• Consequence: SLC52A3 NM_033409.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.254

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=0.0021209419).
• BP6: Variant 20-765553-G-C is Benign according to our data. Variant chr20-765553-G-C is described in ClinVar as [Likely_benign]. Clinvar id is 262231.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-765553-G-C is described in Lovd as [Benign]. Variant chr20-765553-G-C is described in Lovd as [Likely_benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0957 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SLC52A3	NM_033409.4	c.222C>G	p.Ile74Met	missense_variant	2/5	ENST00000645534.1	NP_212134.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SLC52A3	ENST00000645534.1	c.222C>G	p.Ile74Met	missense_variant	2/5		NM_033409.4	ENSP00000494193.1

Frequencies

GnomAD3 genomes AF: 0.0630 AC: 9578 AN: 152122 Hom.: 392 Cov.: 31

Gnomad AFR AF: 0.0171

Gnomad AMI AF: 0.128

Gnomad AMR AF: 0.0606

Gnomad ASJ AF: 0.0441

Gnomad EAS AF: 0.00789

Gnomad SAS AF: 0.0289

Gnomad FIN AF: 0.0664

Gnomad MID AF: 0.0506

Gnomad NFE AF: 0.0977

Gnomad OTH AF: 0.0618

GnomAD3 exomes AF: 0.0648 AC: 12368 AN: 190974 Hom.: 509 AF XY: 0.0646 AC XY: 6560 AN XY: 101606

Gnomad AFR exome AF: 0.0147

Gnomad AMR exome AF: 0.0423

Gnomad ASJ exome AF: 0.0510

Gnomad EAS exome AF: 0.00741

Gnomad SAS exome AF: 0.0360

Gnomad FIN exome AF: 0.0717

Gnomad NFE exome AF: 0.0980

Gnomad OTH exome AF: 0.0694

GnomAD4 exome AF: 0.0909 AC: 129586 AN: 1425206 Hom.: 6489 Cov.: 36 AF XY: 0.0894 AC XY: 63046 AN XY: 705268

Gnomad4 AFR exome AF: 0.0136

Gnomad4 AMR exome AF: 0.0436

Gnomad4 ASJ exome AF: 0.0498

Gnomad4 EAS exome AF: 0.0124

Gnomad4 SAS exome AF: 0.0362

Gnomad4 FIN exome AF: 0.0766

Gnomad4 NFE exome AF: 0.104

Gnomad4 OTH exome AF: 0.0770

GnomAD4 genome AF: 0.0629 AC: 9572 AN: 152238 Hom.: 390 Cov.: 31 AF XY: 0.0602 AC XY: 4484 AN XY: 74428

Gnomad4 AFR AF: 0.0171

Gnomad4 AMR AF: 0.0605

Gnomad4 ASJ AF: 0.0441

Gnomad4 EAS AF: 0.00791

Gnomad4 SAS AF: 0.0281

Gnomad4 FIN AF: 0.0664

Gnomad4 NFE AF: 0.0977

Gnomad4 OTH AF: 0.0611

Alfa AF: 0.0870 Hom.: 457

Bravo AF: 0.0600

TwinsUK AF: 0.103 AC: 382

ALSPAC AF: 0.103 AC: 398

ESP6500AA AF: 0.0189 AC: 83

ESP6500EA AF: 0.0955 AC: 820

ExAC AF: 0.0540 AC: 6484

Asia WGS AF: 0.0190 AC: 68 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Aug 23, 2017	p.Ile74Met in exon 2 of SLC52A3: This variant is not expected to have clinical s ignificance because it has been identified in 12.83% (3040/23690) of European ch romosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute. org; dbSNP rs35655964). -
Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 10, 2018	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Brown-Vialetto-van Laere syndrome 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.53	T
BayesDel_noAF	Benign	-0.44
CADD	Benign	18
DANN	Uncertain	0.99
DEOGEN2	Benign	0.0059	T;T;.;T;T
Eigen	Benign	0.032
Eigen_PC	Benign	0.055
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Benign	0.68	.;.;T;.;T
MetaRNN	Benign	0.0021	T;T;T;T;T
MetaSVM	Benign	-0.81	T
MutationAssessor	Benign	1.4	L;L;L;L;L
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-1.1	.;.;N;N;.
REVEL	Benign	0.26
Sift	Benign	0.092	.;.;T;T;.
Sift4G	Benign	0.090	.;T;T;T;.
Polyphen		0.89	P;P;P;P;P
Vest4		0.088, 0.10
MPC		0.35
ClinPred		0.022	T
GERP RS		2.7
Varity_R		0.086
gMVP		0.52

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

Publications

LitVar

Other links and lift over

dbSNP: rs35655964; hg19: chr20-746197;