rs119473030
Positions:
Variant summary
Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM1PM2PP5
The NM_001126121.2(SLC25A19):āc.530G>Cā(p.Gly177Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000254 in 1,613,940 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (no stars).
Frequency
Genomes: š 0.00023 ( 0 hom., cov: 31)
Exomes š: 0.0000041 ( 0 hom. )
Consequence
SLC25A19
NM_001126121.2 missense
NM_001126121.2 missense
Scores
10
4
3
Clinical Significance
Conservation
PhyloP100: 7.54
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 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 0 benign, 3 uncertain in NM_001126121.2
PM2
?
Very rare variant in population databases, with high coverage;
PP5
?
Variant 17-75278265-C-G is Pathogenic according to our data. Variant chr17-75278265-C-G is described in ClinVar as [Pathogenic]. Clinvar id is 4269.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr17-75278265-C-G is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SLC25A19 | NM_001126121.2 | c.530G>C | p.Gly177Ala | missense_variant | 6/8 | ENST00000416858.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SLC25A19 | ENST00000416858.7 | c.530G>C | p.Gly177Ala | missense_variant | 6/8 | 1 | NM_001126121.2 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.000230 AC: 35AN: 152074Hom.: 0 Cov.: 31
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GnomAD4 exome AF: 0.00000410 AC: 6AN: 1461866Hom.: 0 Cov.: 32 AF XY: 0.00000275 AC XY: 2AN XY: 727226
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GnomAD4 genome ? AF: 0.000230 AC: 35AN: 152074Hom.: 0 Cov.: 31 AF XY: 0.000296 AC XY: 22AN XY: 74310
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:1Other:1
Revision: no assertion criteria provided
LINK: link
Submissions by phenotype
Amish lethal microcephaly Pathogenic:1Other:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Sep 01, 2009 | - - |
not provided, no classification provided | literature only | GeneReviews | - | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Benign
Eigen
Pathogenic
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
LIST_S2
Benign
T;.;.;.;.;T;D
M_CAP
Pathogenic
D
MetaRNN
Uncertain
D;D;D;D;D;D;D
MetaSVM
Pathogenic
D
MutationTaster
Benign
A;A;A;A;A;A
PrimateAI
Uncertain
T
PROVEAN
Pathogenic
D;D;D;D;D;.;.
REVEL
Pathogenic
Sift
Uncertain
D;D;D;D;D;.;.
Sift4G
Pathogenic
D;D;D;D;D;D;.
Polyphen
0.87
.;P;P;P;P;P;.
Vest4
MutPred
0.99
.;Loss of catalytic residue at L178 (P = 0.1126);Loss of catalytic residue at L178 (P = 0.1126);Loss of catalytic residue at L178 (P = 0.1126);Loss of catalytic residue at L178 (P = 0.1126);Loss of catalytic residue at L178 (P = 0.1126);.;
MVP
MPC
0.61
ClinPred
D
GERP RS
Varity_R
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