2-55647421-C-G
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM2PP3_StrongPP5_Very_Strong
The NM_033109.5(PNPT1):āc.1528G>Cā(p.Ala510Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000274 in 1,608,756 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (ā ā ). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A510T) has been classified as Uncertain significance.
Frequency
Consequence
NM_033109.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 16 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PNPT1 | NM_033109.5 | c.1528G>C | p.Ala510Pro | missense_variant | 19/28 | ENST00000447944.7 | |
PNPT1 | XM_005264629.3 | c.1288G>C | p.Ala430Pro | missense_variant | 19/28 | ||
PNPT1 | XM_017005172.2 | c.1288G>C | p.Ala430Pro | missense_variant | 18/27 | ||
PNPT1 | XM_047446161.1 | c.*60G>C | 3_prime_UTR_variant | 20/20 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PNPT1 | ENST00000447944.7 | c.1528G>C | p.Ala510Pro | missense_variant | 19/28 | 1 | NM_033109.5 | P1 |
Frequencies
GnomAD3 genomes AF: 0.0000132 AC: 2AN: 152070Hom.: 0 Cov.: 32
GnomAD4 exome AF: 0.0000288 AC: 42AN: 1456686Hom.: 0 Cov.: 30 AF XY: 0.0000235 AC XY: 17AN XY: 724668
GnomAD4 genome AF: 0.0000132 AC: 2AN: 152070Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74280
ClinVar
Submissions by phenotype
Combined oxidative phosphorylation defect type 13 Pathogenic:2
Pathogenic, no assertion criteria provided | literature only | OMIM | Jul 11, 2022 | - - |
Pathogenic, criteria provided, single submitter | research | Baylor-Hopkins Center for Mendelian Genomics, Johns Hopkins University School of Medicine | - | - - |
not provided Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Invitae | Dec 18, 2022 | In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Studies have shown that this missense change alters PNPT1 gene expression (PMID: 27759031). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt PNPT1 protein function. ClinVar contains an entry for this variant (Variation ID: 253224). This missense change has been observed in individual(s) with combined oxidative phosphorylation deficiency (PMID: 27759031). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces alanine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 510 of the PNPT1 protein (p.Ala510Pro). - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at