2-227699294-C-T

Position:

chr2-227699294-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_025243.4(SLC19A3):c.421G>A(p.Gly141Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00391 in 1,614,090 control chromosomes in the GnomAD database, including 28 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 0.0042 ( 4 hom., cov: 33)

Exomes 𝑓: 0.0039 ( 24 hom. )

Consequence

SLC19A3
NM_025243.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:12

Conservation

PhyloP100: -0.263

Variant links:

Genes affected

SLC19A3 (HGNC:16266): (solute carrier family 19 member 3) This gene encodes a ubiquitously expressed transmembrane thiamine transporter that lacks folate transport activity. Mutations in this gene cause biotin-responsive basal ganglia disease (BBGD); a recessive disorder manifested in childhood that progresses to chronic encephalopathy, dystonia, quadriparesis, and death if untreated. Patients with BBGD have bilateral necrosis in the head of the caudate nucleus and in the putamen. Administration of high doses of biotin in the early progression of the disorder eliminates pathological symptoms while delayed treatment results in residual paraparesis, mild cognitive disability, or dystonia. Administration of thiamine is ineffective in the treatment of this disorder. Experiments have failed to show that this protein can transport biotin. Mutations in this gene also cause a Wernicke's-like encephalopathy.[provided by RefSeq, Jan 2010]

SLC19A3 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.010615945).

BP6

Variant 2-227699294-C-T is Benign according to our data. Variant chr2-227699294-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 139123.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-227699294-C-T is described in Lovd as [Likely_benign]. Variant chr2-227699294-C-T is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00423 (644/152220) while in subpopulation NFE AF= 0.00537 (365/68014). AF 95% confidence interval is 0.00491. There are 4 homozygotes in gnomad4. There are 298 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SLC19A3	NM_025243.4 link	c.421G>A	p.Gly141Ser	missense_variant	3/6	ENST00000644224.2	NP_079519.1	Q9BZV2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SLC19A3	ENST00000644224.2 link	c.421G>A	p.Gly141Ser	missense_variant	3/6		NM_025243.4	ENSP00000495385.1		Q9BZV2

Frequencies

GnomAD3 genomes

AF:

0.00423

AC:

644

AN:

152102

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000724

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00491

Gnomad ASJ

AF:

0.0161

Gnomad EAS

AF:

0.000385

Gnomad SAS

AF:

0.000623

Gnomad FIN

AF:

0.00942

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00537

Gnomad OTH

AF:

0.00575

GnomAD3 exomes

AF:

0.00423

AC:

1064

AN:

251280

Hom.:

AF XY:

0.00414

AC XY:

562

AN XY:

135820

show subpopulations

Gnomad AFR exome

AF:

0.000432

Gnomad AMR exome

AF:

0.00237

Gnomad ASJ exome

AF:

0.0142

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.000784

Gnomad FIN exome

AF:

0.0116

Gnomad NFE exome

AF:

0.00460

Gnomad OTH exome

AF:

0.00522

GnomAD4 exome

AF:

0.00387

AC:

5664

AN:

1461870

Hom.:

Cov.:

AF XY:

0.00388

AC XY:

2824

AN XY:

727230

show subpopulations

Gnomad4 AFR exome

AF:

0.000657

Gnomad4 AMR exome

AF:

0.00264

Gnomad4 ASJ exome

AF:

0.0136

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000904

Gnomad4 FIN exome

AF:

0.00944

Gnomad4 NFE exome

AF:

0.00387

Gnomad4 OTH exome

AF:

0.00440

GnomAD4 genome

AF:

0.00423

AC:

644

AN:

152220

Hom.:

Cov.:

AF XY:

0.00400

AC XY:

298

AN XY:

74426

show subpopulations

Gnomad4 AFR

AF:

0.000722

Gnomad4 AMR

AF:

0.00491

Gnomad4 ASJ

AF:

0.0161

Gnomad4 EAS

AF:

0.000386

Gnomad4 SAS

AF:

0.000624

Gnomad4 FIN

AF:

0.00942

Gnomad4 NFE

AF:

0.00537

Gnomad4 OTH

AF:

0.00569

Alfa

AF:

0.00539

Hom.:

Bravo

AF:

0.00367

TwinsUK

AF:

0.00405

AC:

ALSPAC

AF:

0.00441

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.00593

AC:

ExAC

AF:

0.00376

AC:

457

Asia WGS

AF:

0.000866

AC:

AN:

3478

EpiCase

AF:

0.00632

EpiControl

AF:

0.00652

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Biotin-responsive basal ganglia disease

Benign:5

Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	Feb 12, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign. -
Benign, criteria provided, single submitter	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	Dec 12, 2014	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -

not specified

Benign:4

Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 02, 2013	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Mar 01, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 07, 2016	- -

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Jan 04, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2024	SLC19A3: BP4, BS2 -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Mar 02, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.068

BayesDel_addAF

Benign

-0.48

BayesDel_noAF

Benign

-0.46

CADD

Benign

0.38

DANN

Benign

0.61

DEOGEN2

Benign

0.16

T;T;.;.

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.045

LIST_S2

Benign

0.83

.;T;T;D

MetaRNN

Benign

0.011

T;T;T;T

MetaSVM

Benign

-0.75

MutationAssessor

Benign

0.10

N;N;.;.

PrimateAI

Benign

0.32

PROVEAN

Benign

0.74

.;N;.;.

REVEL

Benign

0.27

Sift

Benign

1.0

.;T;.;.

Sift4G

Benign

1.0

.;T;.;.

Polyphen

0.12

B;B;.;.

Vest4

0.096

MVP

0.55

MPC

0.10

ClinPred

0.0098

GERP RS

-3.5

Varity_R

0.028

gMVP

0.30

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over