rs374698153
Variant summary
Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1PM2PP3_ModeratePP5
The NM_033109.5(PNPT1):āc.1592C>Gā(p.Thr531Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000966 in 1,604,756 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 Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_033109.5 missense
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Likely_pathogenic. Variant got 7 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PNPT1 | NM_033109.5 | c.1592C>G | p.Thr531Arg | missense_variant | 19/28 | ENST00000447944.7 | |
PNPT1 | XM_005264629.3 | c.1352C>G | p.Thr451Arg | missense_variant | 19/28 | ||
PNPT1 | XM_017005172.2 | c.1352C>G | p.Thr451Arg | missense_variant | 18/27 | ||
PNPT1 | XM_047446161.1 | c.*124C>G | 3_prime_UTR_variant | 20/20 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PNPT1 | ENST00000447944.7 | c.1592C>G | p.Thr531Arg | missense_variant | 19/28 | 1 | NM_033109.5 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000791 AC: 12AN: 151782Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000321 AC: 8AN: 249564Hom.: 0 AF XY: 0.0000222 AC XY: 3AN XY: 134968
GnomAD4 exome AF: 0.0000984 AC: 143AN: 1452974Hom.: 0 Cov.: 30 AF XY: 0.0000927 AC XY: 67AN XY: 722620
GnomAD4 genome ? AF: 0.0000791 AC: 12AN: 151782Hom.: 0 Cov.: 32 AF XY: 0.0000944 AC XY: 7AN XY: 74124
ClinVar
Submissions by phenotype
not provided Pathogenic:1Uncertain:2
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | May 20, 2023 | This variant is present in population databases (rs374698153, gnomAD 0.004%). This sequence change replaces threonine, which is neutral and polar, with arginine, which is basic and polar, at codon 531 of the PNPT1 protein (p.Thr531Arg). This missense change has been observed in individuals with combined oxidative phosphorylation deficiency (PMID: 31752325, 33199448; external communication). For these reasons, this variant has been classified as Pathogenic. 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: 209184). - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Apr 21, 2023 | Observed in the heterozygous state in a patient with global developmental delay, intellectual disability, feeding difficulties, irritability, microcephaly, and dystonia who also harbored a second PNPT1 gene variant; the phase of the variants is unknown (Rius et al., 2019); Observed in trans with variant of uncertain significance in the PNPT1 gene in an individual with encephalopathy, developmental delay, and hearing loss (Pennisi A et al., 2020); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at a significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 31752325, 33199448, 36147510, 34740920) - |
Uncertain significance, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Feb 05, 2021 | - - |
Combined oxidative phosphorylation defect type 13 Pathogenic:2
Likely pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Feb 23, 2015 | Likely pathogenicity based on finding it three times in our laboratory in trans with another variant in affacted individuals: a 4-year-old male[with A507S] with global delays, speech articulation disorder, hypotonia; a 6-year-old male [with A507S] with spastic paraplegia, intellectual disability, anosmia, dysphagia, similarly affected sib (who is also compound heterozygous); an 18-year-old male [with V509I] with profound intellectual disability, severe bilateral hearing loss, hypotonia, dysmorphisms, short stature, microcephaly, hyperextensibility, myopia, cataract, congenital heart disease, fused kidneys, small testicles, type II diabetes, immunodeficiency (healthy sib NOT compound heterozygous) - |
Likely pathogenic, criteria provided, single submitter | research | Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard | - | The heterozygous p.Thr531Arg variant in PNPT1 has been identified in the compound heterozygous state by our project in one individual with Combined Oxidative Phosphorylation Deficiency (COPD). The p.Thr531Arg variant has not been reported in the literature, but it has been reported in ClinVar (Variant ID: 209184). Baylor Laboratory reported this variant in 3 probands, however only 1/3 fit the current known clinical spectrum for PNPT1. Functional evidence (PNPase Western Blot, spectrophotometric enzyme assays, Dipstick assays, OXPHOS western blot) supports a pathogenic role for this variant and is consistent with other pathogenic variants (7 publications to date). The spectrophotometric enzyme assays conducted on fibroblasts were normal, which has been observed in other PNPT1- related cases including the one published in EJHG (Alodaib, A., et al. 2016) and others (Vedrenne, V., et al. 2012, Sato, R., et al. 2017). In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic. - |
Autosomal recessive nonsyndromic hearing loss 70 Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 08, 2022 | - - |
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Jul 17, 2022 | The c.1592C>G (p.T531R) alteration is located in exon 19 (coding exon 19) of the PNPT1 gene. This alteration results from a C to G substitution at nucleotide position 1592, causing the threonine (T) at amino acid position 531 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at