rs199558186

Variant names:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_StrongBP6BS1

The NM_025243.4(SLC19A3):c.613A>G(p.Arg205Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000877 in 1,614,062 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00040 ( 1 hom., cov: 32)

Exomes 𝑓: 0.00093 ( 0 hom. )

Consequence

SLC19A3
NM_025243.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:4

Conservation

PhyloP100: 0.706

Publications

5 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 -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.030637175).

BP6

Variant 2-227699102-T-C is Benign according to our data. Variant chr2-227699102-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 334880.

BS1

Variant frequency is greater than expected in population nfe. GnomAdExome4 allele frequency = 0.000926 (1354/1461888) while in subpopulation NFE AF = 0.00117 (1296/1112008). AF 95% confidence interval is 0.00111. There are 0 homozygotes in GnomAdExome4. There are 641 alleles in the male GnomAdExome4 subpopulation. Median coverage is 33. This position passed quality control check.

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
SLC19A3	NM_025243.4	MANE Select	c.613A>G	p.Arg205Gly	missense	Exon 3 of 6	NP_079519.1
SLC19A3	NM_001371411.1		c.613A>G	p.Arg205Gly	missense	Exon 3 of 6	NP_001358340.1
SLC19A3	NM_001371412.1		c.613A>G	p.Arg205Gly	missense	Exon 3 of 6	NP_001358341.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
SLC19A3	ENST00000644224.2	MANE Select	c.613A>G	p.Arg205Gly	missense	Exon 3 of 6	ENSP00000495385.1
SLC19A3	ENST00000258403.8	TSL:1	c.613A>G	p.Arg205Gly	missense	Exon 3 of 6	ENSP00000258403.3
SLC19A3	ENST00000425817.6	TSL:1	n.*638A>G		non_coding_transcript_exon	Exon 5 of 8	ENSP00000397393.2

Frequencies

GnomAD3 genomes

AF:

0.000401

AC:

AN:

152174

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000169

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000524

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000676

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000330

AC:

AN:

251410

AF XY:

0.000375

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.000116

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000462

Gnomad NFE exome

AF:

0.000668

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.000926

AC:

1354

AN:

1461888

Hom.:

Cov.:

AF XY:

0.000881

AC XY:

641

AN XY:

727246

show subpopulations

African (AFR)

AF:

0.000149

AC:

AN:

33480

American (AMR)

AF:

0.000224

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00117

AC:

1296

AN:

1112008

Other (OTH)

AF:

0.000695

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.486

Heterozygous variant carriers

177

265

354

442

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

112

168

224

280

<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:

0.000401

AC:

AN:

152174

Hom.:

Cov.:

AF XY:

0.000484

AC XY:

AN XY:

74358

show subpopulations

African (AFR)

AF:

0.000169

AC:

AN:

41428

American (AMR)

AF:

0.000524

AC:

AN:

15264

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5196

South Asian (SAS)

AF:

0.00

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10620

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.000676

AC:

AN:

68042

Other (OTH)

AF:

0.00

AC:

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.507

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

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:

0.000707

Hom.:

Bravo

AF:

0.000620

TwinsUK

AF:

0.000809

AC:

ALSPAC

AF:

0.00104

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.00105

AC:

ExAC

AF:

0.000329

AC:

EpiCase

AF:

0.000763

EpiControl

AF:

0.000711

ClinVar

ClinVar submissions as Germline

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Biotin-responsive basal ganglia disease (2)

Inborn genetic diseases (1)

Intellectual disability (1)

not provided (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.065

BayesDel_addAF

Benign

-0.39

BayesDel_noAF

Benign

-0.43

CADD

Benign

(source)

DANN

Benign

0.90

DEOGEN2

Benign

0.13

Eigen

Benign

-0.97

Eigen_PC

Benign

-0.94

FATHMM_MKL

Benign

0.073

LIST_S2

Benign

0.28

M_CAP

Benign

0.026

MetaRNN

Benign

0.031

MetaSVM

Benign

-0.94

MutationAssessor

Benign

0.46

PhyloP100

0.71

PrimateAI

Benign

0.19

PROVEAN

Benign

-0.70

REVEL

Benign

0.084

Sift

Benign

0.38

Sift4G

Benign

0.42

Polyphen

0.0

Vest4

0.084

MVP

0.59

MPC

0.070

ClinPred

0.40

GERP RS

0.22

Varity_R

0.057

gMVP

0.18

Mutation Taster

=90/10

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

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over