1-40290870-G-GT

Position:

• chr1-40290870-G-GT

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1 PP5_Very_Strong

The NM_005857.5(ZMPSTE24):​c.1085dupT​(p.Leu362fs) 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 (★★). Synonymous variant affecting the same amino acid position (i.e. L362L) has been classified as Likely benign. 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
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:19 O:1
• 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]

ZMPSTE24 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 16 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PP5: 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	Protein	UniProt
ZMPSTE24	NM_005857.5	c.1085dupT	p.Leu362fs	frameshift_variant	9/10	ENST00000372759.4	NP_005848.2
ZMPSTE24	XM_047427582.1	c.836dupT	p.Leu279fs	frameshift_variant	8/9		XP_047283538.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ZMPSTE24	ENST00000372759.4	c.1085dupT	p.Leu362fs	frameshift_variant	9/10	1	NM_005857.5	ENSP00000361845.3

Frequencies

GnomAD3 genomes AF: 0.000324 AC: 49 AN: 151082 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000974

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000661

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000194

Gnomad SAS AF: 0.000419

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000605

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.000449 AC: 651 AN: 1449326 Hom.: 0 Cov.: 31 AF XY: 0.000447 AC XY: 322 AN XY: 721138

Gnomad4 AFR exome AF: 0.000151

Gnomad4 AMR exome AF: 0.000226

Gnomad4 ASJ exome AF: 0.000116

Gnomad4 EAS exome AF: 0.000179

Gnomad4 SAS exome AF: 0.000210

Gnomad4 FIN exome AF: 0.0000947

Gnomad4 NFE exome AF: 0.000525

Gnomad4 OTH exome AF: 0.000402

GnomAD4 genome AF: 0.000324 AC: 49 AN: 151082 Hom.: 0 Cov.: 31 AF XY: 0.000339 AC XY: 25 AN XY: 73724

Gnomad4 AFR AF: 0.0000974

Gnomad4 AMR AF: 0.0000661

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000194

Gnomad4 SAS AF: 0.000419

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000605

Gnomad4 OTH AF: 0.00

Bravo AF: 0.000302

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:19 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:7 Other:1

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. -
Pathogenic, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	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)	-	- -
not provided, no classification provided	literature only	ZMPSTE24 homepage - Leiden Muscular Dystrophy pages	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jul 24, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2018	- -

Lethal tight skin contracture syndrome Pathogenic:6

Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University Hospital Muenster	Dec 20, 2021	ACMG categories: PVS1,PM2,PM3,PP5 -
Pathogenic, no assertion criteria provided	literature only	OMIM	May 01, 2012	- -
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	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	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	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. -

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	- -

Restrictive dermopathy 1 Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Jul 17, 2023	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with mandibuloacral dysplasia with type B lipodystrophy, (MAD-B; MIM#608612) and restrictive dermopathy 1, (RD; MIM#275210). (I) 0106 - This gene is associated with autosomal recessive disease. Variants that result in residual protein function lead to MAD-B, while complete loss-of-function alleles lead to RD (PMID: 22718200). (I) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction). (SP) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (v2: 93 heterozygotes, 0 homozygotes). (SP) 0701 - Other NMD-predicted variants comparable to the one identified in this case have very strong previous evidence for pathogenicity (DECIPHER). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. It is one of the most common pathogenic variants reported in MAD-B and RD individuals, depending on their second allele (PMID: 24169522, ClinVar). (SP) 1102 - Very strong and specific phenotype match for this individual. (SP) 1206 - This variant has been shown to be paternally inherited (by trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -
Pathogenic, criteria provided, single submitter	clinical testing	Neuberg Centre For Genomic Medicine, NCGM	Jun 22, 2023	The observed frameshift c.1085dup(p.Leu362PhefsTer19) variant in ZMPSTE24 gene has been reported previously in homozygous and compound heterozygous states in multiple individuals affected with restrictive dermopathy (Kwan JM., 2015; Navarro CL, et al., 2014; Loucks C, et al., 2012; Ahmad Z, et al., 2012). This variant has also been observed to segregate with disease in related individuals. This variant has been reported to be a common founder variant in Old Colony Mennonite (OCM) and Hutterites (Loucks C, et al., 2012). The p.Leu362PhefsTer19 variant is present with allele frequency of 0.03% in gnomAD Exomes. This variant has been submitted 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 in ZMPSTE24 gene have been previously reported to be disease causing (Navarro CL, et al., 2014; Barrowman J, et al., 2012). For these reasons, this variant has been classified as Pathogenic. -

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

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.13		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs137854889; hg19: chr1-40756542;