rs1554887097
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong
The NM_021830.5(TWNK):c.1121G>A(p.Arg374Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R374W) has been classified as Likely pathogenic.
Frequency
Consequence
NM_021830.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
TWNK | NM_021830.5 | c.1121G>A | p.Arg374Gln | missense_variant | 1/5 | ENST00000311916.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TWNK | ENST00000311916.8 | c.1121G>A | p.Arg374Gln | missense_variant | 1/5 | 1 | NM_021830.5 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD4 exome Cov.: 32
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
not provided Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jul 21, 2021 | Published functional studies in HEK293 cells demonstrate a damaging effect with a reduction of enzyme activity to 25% compared to wild-type (Goffart et al., 2009); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed in large population cohorts (Lek et al., 2016); Located within the linker region of the TWINKLE helicase protein, a region reported to be important for hexamerization and helicase activity (Korhonen et al., 2008) This variant is associated with the following publications: (PMID: 31147703, 26838077, 26979109, 22353293, 20880070, 20479361, 17620490, 16639411, 29264394, 18279890, 20659899, 18971204, 17272269, 20417176, 11431692) - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Oct 04, 2023 | This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 374 of the TWNK protein (p.Arg374Gln). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with autosomal dominant progressive external ophthalmoplegia (PMID: 11431692, 20880070, 32161153). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 426106). 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 TWNK protein function. For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Athena Diagnostics | Oct 07, 2015 | - - |
Mitochondrial disease Pathogenic:1
Pathogenic, no assertion criteria provided | clinical testing | Wellcome Centre for Mitochondrial Research, Newcastle University | Apr 07, 2017 | - - |
Depression;C0162674:Progressive external ophthalmoplegia;C0452138:Bilateral sensorineural hearing impairment;C1527344:Dysphonia;C1865916:Bilateral ptosis;C4021546:Abnormal mitochondria in muscle tissue;C4021726:EMG: myopathic abnormalities;C4025729:Neuromuscular dysphagia Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Centre for Mendelian Genomics, University Medical Centre Ljubljana | Jan 01, 2017 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at