Variant rs281875369 details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1PM2PP5_Moderate

The NM_005857.5(ZMPSTE24):c.691G>T(p.Glu231Ter) variant causes a stop gained change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,386 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

ZMPSTE24
NM_005857.5 stop_gained

Scores

Clinical Significance

Pathogenic criteria provided, single submitter P:1O:1

Conservation

PhyloP100: 9.37

Variant links:

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 links:

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 12 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;

PP5

Variant 1-40271957-G-T is Pathogenic according to our data. Variant chr1-40271957-G-T is described in ClinVar as [Pathogenic]. Clinvar id is 140536.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr1-40271957-G-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
ZMPSTE24	NM_005857.5 linkuse as main transcript	c.691G>T	p.Glu231Ter	stop_gained	6/10	ENST00000372759.4	NP_005848.2
ZMPSTE24	XM_047427582.1 linkuse as main transcript	c.442G>T	p.Glu148Ter	stop_gained	5/9		XP_047283538.1
ZMPSTE24	XM_047427590.1 linkuse as main transcript	c.691G>T	p.Glu231Ter	stop_gained	6/7		XP_047283546.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris
ZMPSTE24	ENST00000372759.4 linkuse as main transcript	c.691G>T	p.Glu231Ter	stop_gained	6/10	1	NM_005857.5	ENSP00000361845	P1
ZMPSTE24	ENST00000675937.1 linkuse as main transcript	c.691G>T	p.Glu231Ter	stop_gained, NMD_transcript_variant	6/11			ENSP00000502683
ZMPSTE24	ENST00000674703.1 linkuse as main transcript	c.*532G>T		3_prime_UTR_variant, NMD_transcript_variant	7/11			ENSP00000501674
ZMPSTE24	ENST00000675754.1 linkuse as main transcript	c.*433G>T		3_prime_UTR_variant, NMD_transcript_variant	7/11			ENSP00000502555

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461386

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

726990

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Asia WGS

AF:

0.000289

AC:

AN:

3476

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1Other:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Mandibuloacral dysplasia with type B lipodystrophy

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Aug 28, 2022

- -

not provided

Other:1

not provided, no classification provided

literature only

ZMPSTE24 homepage - Leiden Muscular Dystrophy pages

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.63

BayesDel_noAF

Pathogenic

0.65

CADD

Pathogenic

DANN

Uncertain

1.0

Eigen

Pathogenic

1.2

Eigen_PC

Pathogenic

1.0

FATHMM_MKL

Pathogenic

0.99

MutationTaster

Benign

1.0

Vest4

0.87

GERP RS

5.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.28

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.28

Position offset: 3

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over