chr1-40290870-G-GT
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1PP5_Very_Strong
The NM_005857.5(ZMPSTE24):c.1085dup(p.Leu362PhefsTer19) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000437 in 1,600,408 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: 𝑓 0.00032 ( 0 hom., cov: 31)
Exomes 𝑓: 0.00045 ( 0 hom. )
Consequence
ZMPSTE24
NM_005857.5 frameshift
NM_005857.5 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 0.923
Genes affected
ZMPSTE24 (HGNC:12877): (zinc metallopeptidase STE24) This gene encodes a member of the peptidase M48A family. The encoded protein is a zinc metalloproteinase involved in the two step post-translational proteolytic cleavage of carboxy terminal residues of farnesylated prelamin A to form mature lamin A. Mutations in this gene have been associated with mandibuloacral dysplasia and restrictive dermopathy. [provided by RefSeq, Jul 2008]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 16 ACMG points.
PVS1
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Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PP5
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Variant 1-40290870-G-GT is Pathogenic according to our data. Variant chr1-40290870-G-GT is described in ClinVar as [Pathogenic]. Clinvar id is 4271.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ZMPSTE24 | NM_005857.5 | c.1085dup | p.Leu362PhefsTer19 | frameshift_variant | 9/10 | ENST00000372759.4 | |
ZMPSTE24 | XM_047427582.1 | c.836dup | p.Leu279PhefsTer19 | frameshift_variant | 8/9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ZMPSTE24 | ENST00000372759.4 | c.1085dup | p.Leu362PhefsTer19 | frameshift_variant | 9/10 | 1 | NM_005857.5 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.000324 AC: 49AN: 151082Hom.: 0 Cov.: 31
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GnomAD4 exome AF: 0.000449 AC: 651AN: 1449326Hom.: 0 Cov.: 31 AF XY: 0.000447 AC XY: 322AN XY: 721138
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:17Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Pathogenic:7Other:1
not provided, no classification provided | literature only | ZMPSTE24 homepage - Leiden Muscular Dystrophy pages | - | - - |
Pathogenic, no assertion criteria provided | clinical testing | Genome Diagnostics Laboratory, University Medical Center Utrecht | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Jul 24, 2023 | - - |
Pathogenic, no assertion criteria provided | clinical testing | Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Jul 01, 2018 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Nov 12, 2023 | This sequence change creates a premature translational stop signal (p.Leu362Phefs*19) in the ZMPSTE24 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in ZMPSTE24 are known to be pathogenic (PMID: 22718200, 24169522). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This premature translational stop signal has been observed in individual(s) with mandibuloacral dysplasia or restrictive dermopathy (PMID: 12913070, 19020898, 21831885, 22495976, 25629449). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 4271). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, no assertion criteria provided | clinical testing | Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC) | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Aug 31, 2018 | The c.1085dupT variant in the ZMPSTE24 gene has been reported previously in association with restrictive dermopathy when present in the homozygous state (Loucks et al., 2012; Dutta and Danda, 2016; De Vos et al., 2011). The c.1085dupT variant causes a frameshift starting with codon Leucine 362, changes this amino acid to a Phenylalanine residue, and creates a premature Stop codon at position 19 of the new reading frame, denoted p.Leu362PhefsX19. This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. Functional studies showed no proteolytic activity for the c.1085dupT variant (Barrowman et al., 2012).The c.1085dupT variant is not observed in large population cohorts (Lek et al., 2016). We interpret c.1085dupT as a pathogenic variant. - |
Lethal tight skin contracture syndrome Pathogenic:6
Pathogenic, criteria provided, single submitter | clinical testing | Undiagnosed Diseases Network, NIH | Jul 31, 2016 | A mosaic c.1077dupT (p.L362fs) pathogenic variant in the ZMPSTE24 gene was detected in this individual. The c.1077dupT change predicts a translation frameshift at residue 362 with subsequent premature translation termination. This variant has been previously reported as disease causing [aka c.1085dupT (p.Phe361fsX379); PMID 12913070, 22718200, 19442658, 21831885, 22495976, 25629449, 19020898].Whole exome sequencing detected both the reference G allele and the variant GT allele at cDNA position 1077 in this patient. The exome sequencing data showed an increased number of the variant reads (n=98) compared to the reference reads (n=20), suggesting mosaicism for this change in the patient. This individual has been reported in PMID: 29341437. - |
Pathogenic, criteria provided, single submitter | clinical testing | Institute of Human Genetics, University of Leipzig Medical Center | Aug 11, 2021 | This variant was identified as compound heterozygous with NM_005857.5:c.50del. - |
Pathogenic, criteria provided, single submitter | clinical testing | Neuberg Centre For Genomic Medicine, NCGM | Mar 01, 2023 | The frameshift c.1085dup (p.Leu362PhefsTer19) variant in ZMPSTE24 gene has been previously reported in homozygous, heterozygous and compound heterozygous states in multiple individuals affected with Restrictive Dermatopathy (Li, 2010; Ahmad et al., 2012; Moulson et al., 2005). The p.Leu362PhefsTer19 variant has been reported with allele frequency of 0.03% in gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes. This variant has been reported to the ClinVar database as Pathogenic (multiple submissions). This variant causes a frameshift starting with codon Leucine 362, changes this amino acid to Phenylalanine residue, and creates a premature Stop codon at position 19 of the new reading frame, denoted p.Leu362PhefsTer19. This variant is predicted to cause loss of normal protein function through protein truncation. Loss of function variants have been previously reported to be disease causing. For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, no assertion criteria provided | literature only | OMIM | May 01, 2012 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Lifecell International Pvt. Ltd | - | A Heterozygous Frameshift variant c.1076_1077insT in Exon 9 of the ZMPSTE24 gene that results in the amino acid substitution p.Leu362fs*19 was identified. The observed variant has a maximum allele frequency of 0.00026% in gnomAD exomes and genomes, respectively. The severity of the impact of this variant on the protein is high, based on the effect of the protein and REVEL score. Rare Exome Variant Ensemble Learner (REVEL) is an ensembl method for predicting the pathogenicity of missense variants based on a combination of scores from 13 individual tools: MutPred, FATHMM v2.3, VEST 3.0, PolyPhen-2, SIFT, PROVEAN, MutationAssessor, MutationTaster, LRT, GERP++, SiPhy, phyloP, and phastCons. The REVEL score for an individual missense variant can range from 0 to 1, with higher scores reflecting greater likelihood that the variant is disease-causing. The variant has been reported to ClinVar as Pathogenic with a status of (2 stars) criteria provided, multiple submitters, no conflicts (Variation ID 4271 as of 2023-01-21). This sequence change creates a premature translational stop signal (p.Leu362Phefs*19) in the ZMPSTE24 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in ZMPSTE24 are known to be pathogenic (Barrowman, Jemima et al., 2012). Additionally, mutations in the gene are associated with restrictive dermopathy and Mandibuloacral dysplasia (Ahmad, Z et al., 2012; Navarro, Claire Laure et al., 2014). Based on the above evidence this variant has been classified as Pathogenic according to the ACMG guidelines. - |
Pathogenic, criteria provided, single submitter | clinical testing | Institute of Human Genetics, University Hospital Muenster | Dec 20, 2021 | ACMG categories: PVS1,PM2,PM3,PP5 - |
Mandibuloacral dysplasia with type B lipodystrophy Pathogenic:2
Pathogenic, no assertion criteria provided | literature only | OMIM | May 01, 2012 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Jul 22, 2022 | - - |
Lethal tight skin contracture syndrome;C1837756:Mandibuloacral dysplasia with type B lipodystrophy Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Jan 10, 2022 | - - |
ZMPSTE24-related disorder Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Oct 13, 2017 | The ZMPSTE24 c.1085dupT (p.Leu362PhefsTer19) variant results in a frameshift and is predicted to result in premature truncation of the protein. The p.Leu362PhefsTer19 variant has been reported in six studies in which it is found in a compound heterozygous state with a missense variant in one individual with mandibuloacral dysplasia (Agarwal et al. 2003) and in a total of 14 individuals with lethal restrictive dermopathy including in six in homozygous state, in one in a compound heterozygous state, and in seven in a heterozygous state (Navarro et al. 2004; Moulson et al. 2005; Li 2010; Loucks et al. 2012; Ahmad et al. 2012). The p.Leu362PhefsTer19 variant was absent from over 500 control chromosomes and is reported at a frequency of 0.00062 in the South Asian population of the Exome Aggregation Consortium. Yeast complementation assays demonstrated that the p.Leu362PhefsTer19 variant protein, unlike wild type, was unable to rescue a growth arrest phenotype and results in only 1% of the wild type protein activity (Barrowman et al. 2012). The variant was also shown to result in a defect in prelamin A processing (Moulson et al. 2005). Based on the collective evidence and the potential impact of frameshift variants, the p.Leu362PhefsTer19 variant is classified as pathogenic for ZMPSTE24-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. - |
Computational scores
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Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at