2-227696012-A-G

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_025243.4(SLC19A3):c.1049T>C(p.Val350Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0241 in 1,614,086 control chromosomes in the GnomAD database, including 2,926 homozygotes. 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 Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar.

Frequency

Genomes: 𝑓 0.084 ( 1489 hom., cov: 33)

Exomes 𝑓: 0.018 ( 1437 hom. )

Consequence

SLC19A3
NM_025243.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 1.47

Publications

12 publications found

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 Gene-Disease associations (from GenCC):

biotin-responsive basal ganglia disease
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, Genomics England PanelApp, G2P
Leigh syndrome
Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
infantile spams-psychomotor retardation-progressive brain atrophy-basal ganglia disease syndrome
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
Leigh syndrome with leukodystrophy
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
thiamine-responsive encephalopathy
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

SLC19A3 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0036124885).

BP6

Variant 2-227696012-A-G is Benign according to our data. Variant chr2-227696012-A-G is described in ClinVar as Benign. ClinVar VariationId is 130320.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.262 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC19A3	NM_025243.4 link	c.1049T>C	p.Val350Ala	missense_variant	Exon 4 of 6	ENST00000644224.2	NP_079519.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC19A3	ENST00000644224.2 link	c.1049T>C	p.Val350Ala	missense_variant	Exon 4 of 6		NM_025243.4	ENSP00000495385.1

Frequencies

GnomAD3 genomes

AF:

0.0836

AC:

12713

AN:

152084

Hom.:

1486

Cov.:

show subpopulations

Gnomad AFR

AF:

0.266

Gnomad AMI

AF:

0.00548

Gnomad AMR

AF:

0.0370

Gnomad ASJ

AF:

0.00691

Gnomad EAS

AF:

0.0227

Gnomad SAS

AF:

0.00746

Gnomad FIN

AF:

0.000282

Gnomad MID

AF:

0.0348

Gnomad NFE

AF:

0.0120

Gnomad OTH

AF:

0.0656

GnomAD2 exomes

AF:

0.0296

AC:

7437

AN:

251454

AF XY:

0.0242

show subpopulations

Gnomad AFR exome

AF:

0.278

Gnomad AMR exome

AF:

0.0176

Gnomad ASJ exome

AF:

0.0111

Gnomad EAS exome

AF:

0.0249

Gnomad FIN exome

AF:

0.00102

Gnomad NFE exome

AF:

0.0124

Gnomad OTH exome

AF:

0.0209

GnomAD4 exome

AF:

0.0179

AC:

26168

AN:

1461884

Hom.:

1437

Cov.:

AF XY:

0.0166

AC XY:

12040

AN XY:

727244

show subpopulations

African (AFR)

AF:

0.274

AC:

9177

AN:

33480

American (AMR)

AF:

0.0190

AC:

848

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0113

AC:

296

AN:

26134

East Asian (EAS)

AF:

0.0225

AC:

892

AN:

39696

South Asian (SAS)

AF:

0.00560

AC:

483

AN:

86258

European-Finnish (FIN)

AF:

0.00157

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.0272

AC:

157

AN:

5768

European-Non Finnish (NFE)

AF:

0.0112

AC:

12496

AN:

1112008

Other (OTH)

AF:

0.0287

AC:

1735

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.482

Heterozygous variant carriers

1284

2568

3851

5135

6419

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

618

1236

1854

2472

3090

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0838

AC:

12750

AN:

152202

Hom.:

1489

Cov.:

AF XY:

0.0815

AC XY:

6065

AN XY:

74428

show subpopulations

African (AFR)

AF:

0.266

AC:

11038

AN:

41474

American (AMR)

AF:

0.0369

AC:

564

AN:

15278

Ashkenazi Jewish (ASJ)

AF:

0.00691

AC:

AN:

3472

East Asian (EAS)

AF:

0.0227

AC:

118

AN:

5190

South Asian (SAS)

AF:

0.00726

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.000282

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.0340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0120

AC:

814

AN:

68030

Other (OTH)

AF:

0.0659

AC:

139

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

495

989

1484

1978

2473

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

114

228

342

456

570

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0330

Hom.:

1439

Bravo

AF:

0.0950

TwinsUK

AF:

0.0105

AC:

ALSPAC

AF:

0.0132

AC:

ESP6500AA

AF:

0.264

AC:

1161

ESP6500EA

AF:

0.0124

AC:

107

ExAC

AF:

0.0344

AC:

4174

Asia WGS

AF:

0.0280

AC:

AN:

3478

EpiCase

AF:

0.0112

EpiControl

AF:

0.0135

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Genetic Services Laboratory, University of Chicago

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed.

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Oct 28, 2013

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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.

Biotin-responsive basal ganglia disease

Benign:2

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

not provided

Benign:2

Feb 24, 2016

Mayo Clinic Laboratories, Mayo Clinic

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.035

BayesDel_addAF

Benign

-0.67

BayesDel_noAF

Benign

-0.59

CADD

Benign

(source)

DANN

Benign

0.25

DEOGEN2

Benign

0.091

T;T;.

Eigen

Benign

-1.5

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.30

LIST_S2

Benign

0.0

.;T;T

MetaRNN

Benign

0.0036

T;T;T

MetaSVM

Benign

-0.99

MutationAssessor

Benign

-2.3

N;N;.

PhyloP100

1.5

PrimateAI

Benign

0.45

PROVEAN

Benign

0.0

.;N;.

REVEL

Benign

0.0

Sift

Pathogenic

0.0

.;T;.

Sift4G

Pathogenic

0.0

.;T;.

Vest4

0.0

ClinPred

0.0023

GERP RS

1.1

Varity_R

0.030

gMVP

0.26

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over