2-227699279-C-T

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 4P and 9B. PM1PM2BP4_StrongBP6BS1

The NM_025243.4(SLC19A3):​c.436G>A​(p.Val146Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000113 in 1,614,070 control chromosomes in the GnomAD database, including 1 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 Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00038 ( 1 hom., cov: 32)
Exomes 𝑓: 0.000085 ( 0 hom. )

Consequence

SLC19A3
NM_025243.4 missense

Scores

19

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:1

Conservation

PhyloP100: -1.70
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -5 ACMG points.

PM1
In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 5 uncertain in NM_025243.4
PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.01532954).
BP6
Variant 2-227699279-C-T is Benign according to our data. Variant chr2-227699279-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 533544.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=2}.
BS1
Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.000381 (58/152292) while in subpopulation AFR AF= 0.00128 (53/41564). AF 95% confidence interval is 0.001. There are 1 homozygotes in gnomad4. There are 32 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
SLC19A3NM_025243.4 linkc.436G>A p.Val146Ile missense_variant Exon 3 of 6 ENST00000644224.2 NP_079519.1 Q9BZV2

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
SLC19A3ENST00000644224.2 linkc.436G>A p.Val146Ile missense_variant Exon 3 of 6 NM_025243.4 ENSP00000495385.1 Q9BZV2

Frequencies

GnomAD3 genomes
AF:
0.000388
AC:
59
AN:
152174
Hom.:
1
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00130
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000655
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:
0.0000588
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.000123
AC:
31
AN:
251210
Hom.:
0
AF XY:
0.000103
AC XY:
14
AN XY:
135784
show subpopulations
Gnomad AFR exome
AF:
0.00154
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.0000653
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000352
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000848
AC:
124
AN:
1461778
Hom.:
0
Cov.:
33
AF XY:
0.0000866
AC XY:
63
AN XY:
727180
show subpopulations
Gnomad4 AFR exome
AF:
0.00194
Gnomad4 AMR exome
AF:
0.0000447
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000580
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000414
Gnomad4 OTH exome
AF:
0.0000662
GnomAD4 genome
AF:
0.000381
AC:
58
AN:
152292
Hom.:
1
Cov.:
32
AF XY:
0.000430
AC XY:
32
AN XY:
74470
show subpopulations
Gnomad4 AFR
AF:
0.00128
Gnomad4 AMR
AF:
0.0000654
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000588
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000220
Hom.:
0
Bravo
AF:
0.000408
ESP6500AA
AF:
0.000908
AC:
4
ESP6500EA
AF:
0.00
AC:
0
ExAC
AF:
0.000165
AC:
20
EpiCase
AF:
0.0000545
EpiControl
AF:
0.00

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:3Benign:1
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not provided Uncertain:2
Jun 11, 2018
Eurofins Ntd Llc (ga)
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Jan 05, 2023
GeneDx
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

SLC19A3-related disorder Uncertain:1
Jun 07, 2024
PreventionGenetics, part of Exact Sciences
Significance: Uncertain significance
Review Status: no assertion criteria provided
Collection Method: clinical testing

The SLC19A3 c.436G>A variant is predicted to result in the amino acid substitution p.Val146Ile. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.13% of alleles in individuals of African descent in gnomAD, including one homozygote. Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Biotin-responsive basal ganglia disease Benign:1
Jan 22, 2025
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.069
BayesDel_addAF
Benign
-0.49
T
BayesDel_noAF
Benign
-0.49
CADD
Benign
0.0020
DANN
Benign
0.82
DEOGEN2
Benign
0.17
T;T;.;.
Eigen
Benign
-1.7
Eigen_PC
Benign
-1.8
FATHMM_MKL
Benign
0.062
N
LIST_S2
Benign
0.66
.;T;T;T
M_CAP
Benign
0.031
D
MetaRNN
Benign
0.015
T;T;T;T
MetaSVM
Benign
-1.1
T
MutationAssessor
Benign
0.27
N;N;.;.
PrimateAI
Benign
0.26
T
PROVEAN
Benign
-0.33
.;N;.;.
REVEL
Benign
0.20
Sift
Benign
0.64
.;T;.;.
Sift4G
Benign
0.65
.;T;.;.
Polyphen
0.0060
B;B;.;.
Vest4
0.073
MVP
0.27
MPC
0.050
ClinPred
0.0059
T
GERP RS
-8.7
Varity_R
0.023
gMVP
0.19

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs147502239; hg19: chr2-228563995; COSMIC: COSV51452079; COSMIC: COSV51452079; API