2-227696095-T-C

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

Scores

2

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:7

Conservation

PhyloP100: -0.746
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 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
SLC19A3NM_025243.4 linkuse as main transcriptc.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
SLC19A3ENST00000644224.2 linkuse as main transcriptc.980-14A>G splice_polypyrimidine_tract_variant, intron_variant NM_025243.4 ENSP00000495385 P1

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
GnomAD3 exomes
AF:
0.0000679
AC:
17
AN:
250410
Hom.:
0
AF XY:
0.0000664
AC XY:
9
AN XY:
135530
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 SAS 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
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.000224
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000116
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000576
Gnomad4 OTH exome
AF:
0.0000497
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
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.000731
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000147
Gnomad4 OTH
AF:
0.000482
Alfa
AF:
0.0000425
Hom.:
0
Bravo
AF:
0.000155

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 submitterclinical testingFulgent Genetics, Fulgent GeneticsFeb 02, 2022- -
Pathogenic, no assertion criteria providedliterature onlyOMIMJan 01, 2010- -
Pathogenic, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 24, 2024This 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 submitterclinical testingRevvity Omics, RevvityJun 25, 2021- -
not provided Pathogenic:3
Pathogenic, criteria provided, single submitterclinical testingGeneDxDec 15, 2023In 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 submitterclinical testingInstitute of Medical Genetics and Applied Genomics, University Hospital TübingenOct 23, 2020- -
Pathogenic, criteria provided, single submitterclinical testingCenter for Pediatric Genomic Medicine, Children's Mercy Hospital and ClinicsJun 01, 2017- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.87
CADD
Benign
0.0030
DANN
Benign
0.46

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

LitVar

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

Other links and lift over

dbSNP: rs200542114; hg19: chr2-228560811; API