rs281875368

Positions:

• chr1-40270090-TTA-T

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PVS1 PM2

The NM_005857.5(ZMPSTE24):​c.592_593del​(p.Ile198LeufsTer19) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as not provided (no stars). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ZMPSTE24 NM_005857.5 frameshift
• Clinical Significance: not provided no classification provided O:1
• Conservation: PhyloP100: 8.89

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 10 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ZMPSTE24	NM_005857.5	c.592_593del	p.Ile198LeufsTer19	frameshift_variant	5/10	ENST00000372759.4
ZMPSTE24	XM_047427582.1	c.343_344del	p.Ile115LeufsTer19	frameshift_variant	4/9
ZMPSTE24	XM_047427590.1	c.592_593del	p.Ile198LeufsTer19	frameshift_variant	5/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ZMPSTE24	ENST00000372759.4	c.592_593del	p.Ile198LeufsTer19	frameshift_variant	5/10	1	NM_005857.5	P1
ZMPSTE24	ENST00000674703.1	c.*433_*434del		3_prime_UTR_variant, NMD_transcript_variant	6/11
ZMPSTE24	ENST00000675754.1	c.*334_*335del		3_prime_UTR_variant, NMD_transcript_variant	6/11
ZMPSTE24	ENST00000675937.1	c.592_593del	p.Ile198LeufsTer19	frameshift_variant, NMD_transcript_variant	5/11

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Significance: not provided

Submissions summary: Other:1

Revision: no classification provided

Submissions by phenotype

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

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs281875368; hg19: chr1-40735762;