2-227696095-T-C
Position:
Variant summary
Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM2PP3PP5_Very_Strong
The NM_025243.4(SLC19A3):c.980-14A>G variant causes a splice polypyrimidine tract, 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 Likely pathogenic (★★).
Frequency
Genomes: 𝑓 0.000086 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000053 ( 0 hom. )
Consequence
SLC19A3
NM_025243.4 splice_polypyrimidine_tract, intron
NM_025243.4 splice_polypyrimidine_tract, intron
Scores
2
Clinical Significance
Conservation
PhyloP100: -0.746
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 Pathogenic. Variant got 11 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PP3
Splicing scoreres supports a deletorius 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 [Likely_pathogenic]. Clinvar id is 446038.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-227696095-T-C is described in Lovd as [Pathogenic]. Variant chr2-227696095-T-C is described in Lovd as [Likely_pathogenic]. Variant chr2-227696095-T-C is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
SLC19A3 | NM_025243.4 | c.980-14A>G | splice_polypyrimidine_tract_variant, intron_variant | ENST00000644224.2 | NP_079519.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
SLC19A3 | ENST00000644224.2 | c.980-14A>G | splice_polypyrimidine_tract_variant, intron_variant | NM_025243.4 | ENSP00000495385 | P1 |
Frequencies
GnomAD3 genomes AF: 0.0000858 AC: 13AN: 151462Hom.: 0 Cov.: 33
GnomAD3 genomes
AF:
AC:
13
AN:
151462
Hom.:
Cov.:
33
Gnomad AFR
AF:
Gnomad AMI
AF:
Gnomad AMR
AF:
Gnomad ASJ
AF:
Gnomad EAS
AF:
Gnomad SAS
AF:
Gnomad FIN
AF:
Gnomad MID
AF:
Gnomad NFE
AF:
Gnomad OTH
AF:
GnomAD3 exomes AF: 0.0000679 AC: 17AN: 250410Hom.: 0 AF XY: 0.0000664 AC XY: 9AN XY: 135530
GnomAD3 exomes
AF:
AC:
17
AN:
250410
Hom.:
AF XY:
AC XY:
9
AN XY:
135530
Gnomad AFR exome
AF:
Gnomad AMR exome
AF:
Gnomad ASJ exome
AF:
Gnomad EAS exome
AF:
Gnomad SAS exome
AF:
Gnomad FIN exome
AF:
Gnomad NFE exome
AF:
Gnomad OTH exome
AF:
GnomAD4 exome AF: 0.0000534 AC: 78AN: 1461250Hom.: 0 Cov.: 34 AF XY: 0.0000495 AC XY: 36AN XY: 726952
GnomAD4 exome
AF:
AC:
78
AN:
1461250
Hom.:
Cov.:
34
AF XY:
AC XY:
36
AN XY:
726952
Gnomad4 AFR exome
AF:
Gnomad4 AMR exome
AF:
Gnomad4 ASJ exome
AF:
Gnomad4 EAS exome
AF:
Gnomad4 SAS exome
AF:
Gnomad4 FIN exome
AF:
Gnomad4 NFE exome
AF:
Gnomad4 OTH exome
AF:
GnomAD4 genome AF: 0.0000858 AC: 13AN: 151462Hom.: 0 Cov.: 33 AF XY: 0.0000947 AC XY: 7AN XY: 73918
GnomAD4 genome
AF:
AC:
13
AN:
151462
Hom.:
Cov.:
33
AF XY:
AC XY:
7
AN XY:
73918
Gnomad4 AFR
AF:
Gnomad4 AMR
AF:
Gnomad4 ASJ
AF:
Gnomad4 EAS
AF:
Gnomad4 SAS
AF:
Gnomad4 FIN
AF:
Gnomad4 NFE
AF:
Gnomad4 OTH
AF:
Alfa
AF:
Hom.:
Bravo
AF:
ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:7
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Biotin-responsive basal ganglia disease Pathogenic:4
Likely pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Feb 02, 2022 | - - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Jan 01, 2010 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 24, 2024 | 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 disrupted 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. - |
Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Jun 25, 2021 | - - |
not provided Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Dec 15, 2023 | In silico analysis supports a deleterious effect on splicing; 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, 34631424, 35094435, 32600842) - |
Pathogenic, criteria provided, single submitter | clinical testing | Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen | Oct 23, 2020 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics | Jun 01, 2017 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_AG_spliceai
Position offset: -1
DS_AL_spliceai
Position offset: -14
Find out detailed SpliceAI scores and Pangolin per-transcript scores at