rs312262686

Positions:

• chr1-40270128-G-C

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_Strong PM2 PP5_Very_Strong

The NM_005857.5(ZMPSTE24):​c.627+1G>C variant causes a splice donor, intron 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. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: ZMPSTE24 NM_005857.5 splice_donor, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:2 O:1
• Conservation: PhyloP100: 9.54

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]

ACMG classification

Verdict is Pathogenic. Variant got 14 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.10644258 fraction of the gene. Cryptic splice site detected, with MaxEntScore 6.3, offset of 44, new splice context is: ttgGTgaga. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in inframe change.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 1-40270128-G-C is Pathogenic according to our data. Variant chr1-40270128-G-C is described in ClinVar as [Pathogenic]. Clinvar id is 140532.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-40270128-G-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ZMPSTE24	NM_005857.5	c.627+1G>C		splice_donor_variant, intron_variant		ENST00000372759.4	NP_005848.2
ZMPSTE24	XM_047427582.1	c.378+1G>C		splice_donor_variant, intron_variant			XP_047283538.1
ZMPSTE24	XM_047427590.1	c.627+1G>C		splice_donor_variant, intron_variant			XP_047283546.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ZMPSTE24	ENST00000372759.4	c.627+1G>C		splice_donor_variant, intron_variant		1	NM_005857.5	ENSP00000361845.3
ZMPSTE24	ENST00000674703.1	n.*468+1G>C		splice_donor_variant, intron_variant				ENSP00000501674.1
ZMPSTE24	ENST00000675754.1	n.*369+1G>C		splice_donor_variant, intron_variant				ENSP00000502555.1
ZMPSTE24	ENST00000675937.1	n.627+1G>C		splice_donor_variant, intron_variant				ENSP00000502683.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Mandibuloacral dysplasia with type B lipodystrophy Pathogenic:1

Pathogenic, criteria provided, single submitter

research

Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital

Oct 04, 2024

PVS1,PM2,PS3 -

Lethal tight skin contracture syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Genetic Diagnostics Department, Viafet Genomics Laboratory

Aug 23, 2021

As part of Carrier Screening testing performed at Viafet Genomics Laboratory, this variant was identified in a heterozygous state in 3 family members who are not affected with this condition. This variant is present in exon 5/10 in the only transcript of this gene. Several loss-of-function variants are reported as disease-causing in HGMD and/or ClinVar after this position. Sander et al., 2008 have identified this variant in a homozygous state in two patients affected with restrictive myopathy. Mutant mRNA expression studies have shown an in-frame exon 5 skipping (PMID: 18671782). -

not provided Other:1

not provided, no classification provided

literature only

ZMPSTE24 homepage - Leiden Muscular Dystrophy pages

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.39
CADD	Pathogenic	34
DANN	Uncertain	1.0
Eigen	Pathogenic	1.3
Eigen_PC	Pathogenic	1.1
FATHMM_MKL	Pathogenic	0.99	D
GERP RS		5.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.8

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.94
SpliceAI score (max)		0.99		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.99		Position offset: -1

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

Publications

LitVar

Other links and lift over

dbSNP: rs312262686; hg19: chr1-40735800;