chr2-227696095-T-C

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PP3PP5_Very_Strong

The NM_025243.4(SLC19A3):​c.980-14A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000564 in 1,612,712 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).

Frequency

Genomes: 𝑓 0.000086 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000053 ( 0 hom. )

Consequence

SLC19A3
NM_025243.4 intron

Scores

2

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:7

Conservation

PhyloP100: -0.746

Publications

9 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

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 9 ACMG points.

PP3
Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
PP5
Variant 2-227696095-T-C is Pathogenic according to our data. Variant chr2-227696095-T-C is described in ClinVar as Pathogenic. ClinVar VariationId is 446038.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
SLC19A3NM_025243.4 linkc.980-14A>G 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
SLC19A3ENST00000644224.2 linkc.980-14A>G intron_variant Intron 3 of 5 NM_025243.4 ENSP00000495385.1 Q9BZV2

Frequencies

GnomAD3 genomes
AF:
0.0000858
AC:
13
AN:
151462
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000731
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:
0.0000147
Gnomad OTH
AF:
0.000482
GnomAD2 exomes
AF:
0.0000679
AC:
17
AN:
250410
AF XY:
0.0000664
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.000262
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000706
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000534
AC:
78
AN:
1461250
Hom.:
0
Cov.:
34
AF XY:
0.0000495
AC XY:
36
AN XY:
726952
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
33460
American (AMR)
AF:
0.000224
AC:
10
AN:
44716
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
26128
East Asian (EAS)
AF:
0.00
AC:
0
AN:
39692
South Asian (SAS)
AF:
0.0000116
AC:
1
AN:
86236
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
53418
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5764
European-Non Finnish (NFE)
AF:
0.0000576
AC:
64
AN:
1111462
Other (OTH)
AF:
0.0000497
AC:
3
AN:
60374
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.480
Heterozygous variant carriers
0
6
12
18
24
30
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Variant carriers
0
2
4
6
8
10
<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:
0.0000858
AC:
13
AN:
151462
Hom.:
0
Cov.:
33
AF XY:
0.0000947
AC XY:
7
AN XY:
73918
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
41394
American (AMR)
AF:
0.000731
AC:
11
AN:
15046
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
3462
East Asian (EAS)
AF:
0.00
AC:
0
AN:
5146
South Asian (SAS)
AF:
0.00
AC:
0
AN:
4782
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
10490
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
312
European-Non Finnish (NFE)
AF:
0.0000147
AC:
1
AN:
67850
Other (OTH)
AF:
0.000482
AC:
1
AN:
2074
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.540
Heterozygous variant carriers
0
1
2
4
5
6
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Genome Het
Variant carriers
0
2
4
6
8
10
<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:
0.0000543
Hom.:
0
Bravo
AF:
0.000155

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:7
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Biotin-responsive basal ganglia disease Pathogenic:4
Dec 21, 2023
Fulgent Genetics, Fulgent Genetics
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Jan 27, 2025
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This sequence change falls in intron 3 of the SLC19A3 gene. It does not directly change the encoded amino acid sequence of the SLC19A3 protein. RNA analysis indicates that this variant induces altered splicing and may result in an absent or altered protein product. This variant is present in population databases (rs200542114, gnomAD 0.02%). This variant has been observed in individuals with thiamine metabolism dysfunction syndrome 2, also known as biotin-responsive basal ganglia disease (PMID: 20065143, 22777947, 24957181, 26657515). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 446038). Studies have shown that this variant alters mRNA splicing and is expected to lead to the loss of protein expression (PMID: 20065143, 26657515). For these reasons, this variant has been classified as Pathogenic. -

Jan 01, 2010
OMIM
Significance:Pathogenic
Review Status:no assertion criteria provided
Collection Method:literature only

- -

Jun 25, 2021
Revvity Omics, Revvity
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

not provided Pathogenic:3
Oct 23, 2020
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Jun 01, 2017
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Dec 29, 2024
GeneDx
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing

Published functional studies demonstrate a damaging effect (PMID: 20065143); This variant is associated with the following publications: (PMID: 27621386, 24957181, 20065143, 26657515, 31589614, 31440721, 31557427, 34352085, 31061755, 31095747, 34276785, 35094435, 34631424, 32600842, 22777947) -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.87
CADD
Benign
0.0030
DANN
Benign
0.46
PhyloP100
-0.75
Mutation Taster
=11/89
disease causing (ClinVar)

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.75
Details are displayed if max score is > 0.2
DS_AG_spliceai
0.23
Position offset: -1
DS_AL_spliceai
0.75
Position offset: -14

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

Other links and lift over

dbSNP: rs200542114; hg19: chr2-228560811; API