17-75278173-G-A
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Variant summary
Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate
The NM_001126121.2(SLC25A19):c.622C>T(p.Pro208Ser) variant causes a missense change. The variant allele was found at a frequency of 0.000319 in 1,613,718 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Genomes: 𝑓 0.00020 ( 0 hom., cov: 31)
Exomes 𝑓: 0.00033 ( 1 hom. )
Consequence
SLC25A19
NM_001126121.2 missense
NM_001126121.2 missense
Scores
3
14
Clinical Significance
Conservation
PhyloP100: 5.36
Genes affected
SLC25A19 (HGNC:14409): (solute carrier family 25 member 19) This gene encodes a mitochondrial protein that is a member of the solute carrier family. Although this protein was initially thought to be the mitochondrial deoxynucleotide carrier involved in the uptake of deoxynucleotides into the matrix of the mitochondria, further studies have demonstrated that this protein instead functions as the mitochondrial thiamine pyrophosphate carrier, which transports thiamine pyrophosphates into mitochondria. Mutations in this gene cause microcephaly, Amish type, a metabolic disease that results in severe congenital microcephaly, severe 2-ketoglutaric aciduria, and death within the first year. Multiple alternatively spliced variants, encoding the same protein, have been identified for this gene. [provided by RefSeq, Jul 2008]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 0 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.15283394).
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SLC25A19 | NM_001126121.2 | c.622C>T | p.Pro208Ser | missense_variant | 6/8 | ENST00000416858.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SLC25A19 | ENST00000416858.7 | c.622C>T | p.Pro208Ser | missense_variant | 6/8 | 1 | NM_001126121.2 | P1 |
Frequencies
GnomAD3 genomes AF: 0.000204 AC: 31AN: 152126Hom.: 0 Cov.: 31
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GnomAD3 exomes AF: 0.000155 AC: 39AN: 251346Hom.: 0 AF XY: 0.000140 AC XY: 19AN XY: 135900
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GnomAD4 exome AF: 0.000331 AC: 484AN: 1461592Hom.: 1 Cov.: 32 AF XY: 0.000326 AC XY: 237AN XY: 727088
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GnomAD4 genome AF: 0.000204 AC: 31AN: 152126Hom.: 0 Cov.: 31 AF XY: 0.000215 AC XY: 16AN XY: 74318
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:6
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Uncertain:4
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Mar 18, 2022 | This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 208 of the SLC25A19 protein (p.Pro208Ser). This variant is present in population databases (rs200276538, gnomAD 0.03%). This variant has not been reported in the literature in individuals affected with SLC25A19-related conditions. ClinVar contains an entry for this variant (Variation ID: 96021). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Athena Diagnostics | Jun 15, 2018 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Aug 12, 2013 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Jul 30, 2018 | A variant of uncertain significance has been identified in the SLC25A19 gene. The P208S variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The P208S variant is observed in 12/65896 (0.02%) alleles from individuals of European background (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The P208S variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved in mammals. However, in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant. - |
Amish lethal microcephaly Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 13, 2018 | This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. - |
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Jun 17, 2022 | The c.622C>T (p.P208S) alteration is located in exon 6 (coding exon 4) of the SLC25A19 gene. This alteration results from a C to T substitution at nucleotide position 622, causing the proline (P) at amino acid position 208 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Uncertain
CADD
Benign
DANN
Benign
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Uncertain
D
LIST_S2
Benign
T;.;.;.;.;T
M_CAP
Benign
D
MetaRNN
Benign
T;T;T;T;T;T
MetaSVM
Benign
T
MutationTaster
Benign
D;D;D;D;D;D
PrimateAI
Benign
T
PROVEAN
Benign
N;N;N;N;N;.
REVEL
Uncertain
Sift
Benign
T;T;T;T;T;.
Sift4G
Benign
T;T;T;T;T;T
Polyphen
0.029
.;B;B;B;B;B
Vest4
MVP
MPC
0.15
ClinPred
T
GERP RS
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gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at