1-40258299-T-TA

Position:

• chr1-40258299-T-TA

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_005857.5(ZMPSTE24):​c.28_29insA​(p.Leu10fs) variant causes a frameshift change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: ZMPSTE24 NM_005857.5 frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 6.60

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 12 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 43 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 1-40258299-T-TA is Pathogenic according to our data. Variant chr1-40258299-T-TA is described in ClinVar as [Pathogenic]. Clinvar id is 2711294.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ZMPSTE24	NM_005857.5	c.28_29insA	p.Leu10fs	frameshift_variant	1/10	ENST00000372759.4	NP_005848.2
ZMPSTE24	XM_047427590.1	c.28_29insA	p.Leu10fs	frameshift_variant	1/7		XP_047283546.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ZMPSTE24	ENST00000372759.4	c.28_29insA	p.Leu10fs	frameshift_variant	1/10	1	NM_005857.5	ENSP00000361845.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 29, 2024

This sequence change creates a premature translational stop signal (p.Leu10Tyrfs*37) 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). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with mandibuloacral dysplasia with type B lipodystrophy (PMID: 35597529). It has also been observed to segregate with disease in related individuals. For these reasons, this variant has been classified as Pathogenic. -

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr1-40723971;