2-227696084-GAA-GA

Variant names:

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_StrongBA1

The NM_025243.4(SLC19A3):c.980-4delT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.95 ( 68683 hom., cov: 0)

Exomes 𝑓: 0.99 ( 723316 hom. )

Consequence

SLC19A3
NM_025243.4 splice_region, intron

Scores

Not classified

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:12

Conservation

PhyloP100: 0.0760

Publications

10 publications found

Variant links:

COSMIC-nc: COSV108048152

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 -16 ACMG points.

BP6

Variant 2-227696084-GA-G is Benign according to our data. Variant chr2-227696084-GA-G is described in ClinVar as Benign. ClinVar VariationId is 215155.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.993 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC19A3	NM_025243.4 link	c.980-4delT		splice_region_variant, intron_variant	Intron 3 of 5	ENST00000644224.2	NP_079519.1	Q9BZV2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC19A3	ENST00000644224.2 link	c.980-4delT		splice_region_variant, intron_variant	Intron 3 of 5		NM_025243.4	ENSP00000495385.1		Q9BZV2

Frequencies

GnomAD3 genomes

AF:

0.947

AC:

143939

AN:

152024

Hom.:

68660

Cov.:

show subpopulations

Gnomad AFR

AF:

0.816

Gnomad AMI

AF:

1.00

Gnomad AMR

AF:

0.978

Gnomad ASJ

AF:

1.00

Gnomad EAS

AF:

1.00

Gnomad SAS

AF:

0.999

Gnomad FIN

AF:

1.00

Gnomad MID

AF:

0.994

Gnomad NFE

AF:

0.999

Gnomad OTH

AF:

0.964

GnomAD2 exomes

AF:

0.986

AC:

247116

AN:

250528

AF XY:

0.990

show subpopulations

Gnomad AFR exome

AF:

0.810

Gnomad AMR exome

AF:

0.992

Gnomad ASJ exome

AF:

1.00

Gnomad EAS exome

AF:

1.00

Gnomad FIN exome

AF:

1.00

Gnomad NFE exome

AF:

1.00

Gnomad OTH exome

AF:

0.994

GnomAD4 exome

AF:

0.995

AC:

1453354

AN:

1461204

Hom.:

723316

Cov.:

AF XY:

0.995

AC XY:

723698

AN XY:

726984

show subpopulations

African (AFR)

AF:

0.810

AC:

27066

AN:

33434

American (AMR)

AF:

0.991

AC:

44286

AN:

44680

Ashkenazi Jewish (ASJ)

AF:

1.00

AC:

26129

AN:

26130

East Asian (EAS)

AF:

1.00

AC:

39684

AN:

39684

South Asian (SAS)

AF:

1.00

AC:

86213

AN:

86246

European-Finnish (FIN)

AF:

1.00

AC:

53412

AN:

53412

Middle Eastern (MID)

AF:

0.993

AC:

5724

AN:

5764

European-Non Finnish (NFE)

AF:

1.00

AC:

1111285

AN:

1111484

Other (OTH)

AF:

0.987

AC:

59555

AN:

60370

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.489

Heterozygous variant carriers

349

698

1046

1395

1744

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

21652

43304

64956

86608

108260

<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:

0.947

AC:

144021

AN:

152142

Hom.:

68683

Cov.:

AF XY:

0.949

AC XY:

70610

AN XY:

74392

show subpopulations

African (AFR)

AF:

0.815

AC:

33789

AN:

41442

American (AMR)

AF:

0.978

AC:

14948

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

1.00

AC:

3470

AN:

3470

East Asian (EAS)

AF:

1.00

AC:

5176

AN:

5176

South Asian (SAS)

AF:

1.00

AC:

4816

AN:

4818

European-Finnish (FIN)

AF:

1.00

AC:

10602

AN:

10602

Middle Eastern (MID)

AF:

0.997

AC:

293

AN:

294

European-Non Finnish (NFE)

AF:

0.999

AC:

67978

AN:

68030

Other (OTH)

AF:

0.964

AC:

2037

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

321

642

962

1283

1604

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

908

1816

2724

3632

4540

<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:

0.977

Hom.:

13221

Bravo

AF:

0.940

EpiCase

AF:

1.00

EpiControl

AF:

1.00

ClinVar

Significance: Benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:6

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jul 15, 2024

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is classified as Benign based on local population frequency. This variant was detected in 99% of patients studied in a panel designed for Epileptic and Developmental Encephalopathy and Progressive Myoclonus Epilepsy. Number of patients: 92. Only high quality variants are reported. -

Jun 10, 2016

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Sep 10, 2013

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The variant is found in MITONUC-MITOP panel(s). -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Biotin-responsive basal ganglia disease

Benign:3

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jul 15, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 28, 2019

Mendelics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:2

Apr 20, 2017

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 19, 2016

Mayo Clinic Laboratories, Mayo Clinic

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Thiamine Metabolism Dysfunction Syndrome

Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

0.076

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.050

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