Genetic Variant SLC19A3:p.Ser145Ser (chr2-227699280-G-A) – ACMG Classification: Benign (-21 pts)

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_025243.4(SLC19A3):c.435C>T(p.Ser145Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00762 in 1,613,926 control chromosomes in the GnomAD database, including 759 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.041 ( 438 hom., cov: 32)

Exomes 𝑓: 0.0041 ( 321 hom. )

Consequence

SLC19A3
NM_025243.4 synonymous

Scores

Clinical Significance

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

Conservation

PhyloP100: -1.07

Publications

1 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:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.76).

BP6

Variant 2-227699280-G-A is Benign according to our data. Variant chr2-227699280-G-A is described in ClinVar as Benign. ClinVar VariationId is 130323.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-1.07 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.14 is higher than 0.05.

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.435C>T	p.Ser145Ser	synonymous	Exon 3 of 6	NP_079519.1	Q9BZV2
SLC19A3	NM_001371411.1		c.435C>T	p.Ser145Ser	synonymous	Exon 3 of 6	NP_001358340.1	Q9BZV2
SLC19A3	NM_001371412.1		c.435C>T	p.Ser145Ser	synonymous	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.435C>T	p.Ser145Ser	synonymous	Exon 3 of 6	ENSP00000495385.1	Q9BZV2
SLC19A3	ENST00000258403.8	TSL:1	c.435C>T	p.Ser145Ser	synonymous	Exon 3 of 6	ENSP00000258403.3	Q9BZV2
SLC19A3	ENST00000425817.6	TSL:1	n.*460C>T		non_coding_transcript_exon	Exon 5 of 8	ENSP00000397393.2	E7EM61

Frequencies

GnomAD3 genomes

AF:

0.0411

AC:

6251

AN:

152022

Hom.:

438

Cov.:

show subpopulations

Gnomad AFR

AF:

0.143

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0168

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000621

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.000529

Gnomad OTH

AF:

0.0287

GnomAD2 exomes

AF:

0.0107

AC:

2685

AN:

251168

AF XY:

0.00745

show subpopulations

Gnomad AFR exome

AF:

0.148

Gnomad AMR exome

AF:

0.00607

Gnomad ASJ exome

AF:

0.0000993

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000282

Gnomad OTH exome

AF:

0.00440

GnomAD4 exome

AF:

0.00412

AC:

6020

AN:

1461786

Hom.:

321

Cov.:

AF XY:

0.00348

AC XY:

2531

AN XY:

727182

show subpopulations

African (AFR)

AF:

0.145

AC:

4870

AN:

33480

American (AMR)

AF:

0.00713

AC:

319

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.0000383

AC:

AN:

26136

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39700

South Asian (SAS)

AF:

0.000267

AC:

AN:

86252

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53384

Middle Eastern (MID)

AF:

0.00537

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000131

AC:

146

AN:

1111950

Other (OTH)

AF:

0.0104

AC:

629

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.466

Heterozygous variant carriers

365

730

1094

1459

1824

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

148

296

444

592

740

<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:

0.0412

AC:

6274

AN:

152140

Hom.:

438

Cov.:

AF XY:

0.0392

AC XY:

2917

AN XY:

74394

show subpopulations

African (AFR)

AF:

0.143

AC:

5917

AN:

41464

American (AMR)

AF:

0.0168

AC:

257

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5170

South Asian (SAS)

AF:

0.000414

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10604

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000529

AC:

AN:

68008

Other (OTH)

AF:

0.0289

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

279

558

836

1115

1394

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

116

174

232

290

<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:

0.00251

Hom.:

Bravo

AF:

0.0459

EpiCase

AF:

0.000327

EpiControl

AF:

0.000178

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (4)

Biotin-responsive basal ganglia disease (2)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.76

CADD

Benign

0.21

(source)

DANN

Benign

0.63

PhyloP100

-1.1

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over