Genetic Variant SLC19A3:p.Gly141Ser (chr2-227699294-C-T) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -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. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G141C) has been classified as Uncertain significance.

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

Publications

7 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: Orphanet, PanelApp Australia, G2P, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
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=0.010615945).

BP6

Variant 2-227699294-C-T is Benign according to our data. Variant chr2-227699294-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 139123.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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 the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 4 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_025243.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SLC19A3	NM_025243.4	MANE Select	c.421G>A	p.Gly141Ser	missense	Exon 3 of 6	NP_079519.1	Q9BZV2
SLC19A3	NM_001371411.1		c.421G>A	p.Gly141Ser	missense	Exon 3 of 6	NP_001358340.1	Q9BZV2
SLC19A3	NM_001371412.1		c.421G>A	p.Gly141Ser	missense	Exon 3 of 6	NP_001358341.1	Q9BZV2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SLC19A3	ENST00000644224.2	MANE Select	c.421G>A	p.Gly141Ser	missense	Exon 3 of 6	ENSP00000495385.1	Q9BZV2
SLC19A3	ENST00000258403.8	TSL:1	c.421G>A	p.Gly141Ser	missense	Exon 3 of 6	ENSP00000258403.3	Q9BZV2
SLC19A3	ENST00000425817.6	TSL:1	n.*446G>A		non_coding_transcript_exon	Exon 5 of 8	ENSP00000397393.2	E7EM61

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

GnomAD2 exomes

AF:

0.00423

AC:

1064

AN:

251280

AF XY:

0.00414

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 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

African (AFR)

AF:

0.000657

AC:

AN:

33478

American (AMR)

AF:

0.00264

AC:

118

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0136

AC:

356

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.000904

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00944

AC:

504

AN:

53408

Middle Eastern (MID)

AF:

0.00208

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00387

AC:

4308

AN:

1112002

Other (OTH)

AF:

0.00440

AC:

266

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.483

Heterozygous variant carriers

362

723

1085

1446

1808

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

144

288

432

576

720

<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:

0.00423

AC:

644

AN:

152220

Hom.:

Cov.:

AF XY:

0.00400

AC XY:

298

AN XY:

74426

show subpopulations

African (AFR)

AF:

0.000722

AC:

AN:

41530

American (AMR)

AF:

0.00491

AC:

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.0161

AC:

AN:

3472

East Asian (EAS)

AF:

0.000386

AC:

AN:

5178

South Asian (SAS)

AF:

0.000624

AC:

AN:

4810

European-Finnish (FIN)

AF:

0.00942

AC:

100

AN:

10616

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00537

AC:

365

AN:

68014

Other (OTH)

AF:

0.00569

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

103

138

172

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<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:

0.00475

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

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Biotin-responsive basal ganglia disease (5)

not specified (4)

not provided (3)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.068

BayesDel_addAF

Benign

-0.48

BayesDel_noAF

Benign

-0.46

CADD

Benign

0.38

(source)

DANN

Benign

0.61

DEOGEN2

Benign

0.16

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.045

LIST_S2

Benign

0.83

MetaRNN

Benign

0.011

MetaSVM

Benign

-0.75

MutationAssessor

Benign

0.10

PhyloP100

-0.26

PrimateAI

Benign

0.32

PROVEAN

Benign

0.74

REVEL

Benign

0.27

Sift

Benign

1.0

Sift4G

Benign

1.0

Polyphen

0.12

Vest4

0.096

MVP

0.55

MPC

0.10

ClinPred

0.0098

GERP RS

-3.5

Varity_R

0.028

gMVP

0.30

Mutation Taster

=97/3

polymorphism

(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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over