rs769114543
Variant summary
Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2PP3_StrongPP5
The NM_144988.4(ALG14):c.220G>A(p.Asp74Asn) variant causes a missense change. The variant allele was found at a frequency of 0.000229 in 1,613,706 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). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D74E) has been classified as Uncertain significance.
Frequency
Consequence
NM_144988.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 7 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ALG14 | NM_144988.4 | c.220G>A | p.Asp74Asn | missense_variant | 2/4 | ENST00000370205.6 | |
ALG14-AS1 | NR_132786.1 | n.595-2110C>T | intron_variant, non_coding_transcript_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ALG14 | ENST00000370205.6 | c.220G>A | p.Asp74Asn | missense_variant | 2/4 | 1 | NM_144988.4 | P1 | |
ALG14-AS1 | ENST00000451611.1 | n.595-2110C>T | intron_variant, non_coding_transcript_variant | 1 | |||||
ALG14 | ENST00000495856.1 | n.196G>A | non_coding_transcript_exon_variant | 2/4 | 3 |
Frequencies
GnomAD3 genomes ? AF: 0.000112 AC: 17AN: 152174Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.000155 AC: 39AN: 251082Hom.: 0 AF XY: 0.0000811 AC XY: 11AN XY: 135676
GnomAD4 exome AF: 0.000241 AC: 352AN: 1461532Hom.: 0 Cov.: 30 AF XY: 0.000219 AC XY: 159AN XY: 727090
GnomAD4 genome ? AF: 0.000112 AC: 17AN: 152174Hom.: 0 Cov.: 33 AF XY: 0.0000673 AC XY: 5AN XY: 74340
ClinVar
Submissions by phenotype
not provided Pathogenic:1Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Jul 27, 2017 | The D74N variant in the ALG14 gene has been reported previously when present in the homozygous state or when in trans with another variant in affected individuals with severe muscular hypotonia, progressive cerebral atrophy, and therapy-refractory epilepsy (Schorling et al., 2017). The D74N variant is observed in 4/11518 (0.03%) alleles from individuals of Latino background and in 16/66558 (0.02%) alleles from individuals of non-Finnish European background, in the ExAC dataset (Lek et al., 2016). The D74N variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. We interpret D74N as a variant of uncertain significance. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Jun 21, 2022 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Athena Diagnostics | Dec 31, 2020 | This variant segregates with disease in multiple families (PMID 28733338). The frequency of this variant in the general population is consistent with being disease causing. (http://gnomad.broadinstitute.org). Computational tools yielded predictions that this amino acid change may be damaging to the protein.This observation is not an independent occurrence and has been identified in the same individual by RCIGM, the other laboratory participating in the GEMINI study. - |
Myopathy, epilepsy, and progressive cerebral atrophy Pathogenic:2
Pathogenic, no assertion criteria provided | literature only | OMIM | Oct 05, 2020 | - - |
Likely pathogenic, criteria provided, single submitter | curation | SIB Swiss Institute of Bioinformatics | Apr 13, 2021 | This variant is interpreted as likely pathogenic for Myopathy, epilepsy, and progressive cerebral atrophy, autosomal recessive. The following ACMG Tag(s) were applied: Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium (PM2); Cosegregation with disease in multiple affected family members in a gene definitively known to cause the disease (PP1); Multiple lines of computational evidence support a deleterious effect on the gene or gene product (PP3); For recessive disorders, detected in trans with a pathogenic variant (PM3). - |
See cases Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Institute of Human Genetics, University Hospital Muenster | Jun 27, 2024 | ACMG categories: PS3,PS4,PP3 - |
Congenital myasthenic syndrome 15 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Sep 12, 2023 | For these reasons, this variant has been classified as Pathogenic. This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 74 of the ALG14 protein (p.Asp74Asn). This variant is present in population databases (rs769114543, gnomAD 0.03%). This missense change has been observed in individuals with severe neurodegeneration with myopathic and myasthenic features (PMID: 28733338). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 389968). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. - |
Congenital myopathy Pathogenic:1
Pathogenic, criteria provided, single submitter | research | Muscle and Diseases Team, Institut de Génétique et Biologie Moléculaire et Cellulaire | Mar 01, 2024 | PS1+PM2+PM3+PP3+PP5 - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at