rs281875371

Positions:

chr1-40281367-A-G

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PS1_ModeratePM1PP3_StrongPP5_Moderate

The NM_005857.5(ZMPSTE24):c.794A>G(p.Asn265Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000204 in 1,614,006 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 (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely pathogenicin UniProt.

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000021 ( 0 hom. )

Consequence

ZMPSTE24
NM_005857.5 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 8.62

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 10 ACMG points.

PS1

Transcript NM_005857.5 (ZMPSTE24) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in UniProt

PM1

In a topological_domain Nuclear (size 130) in uniprot entity FACE1_HUMAN there are 9 pathogenic changes around while only 0 benign (100%) in NM_005857.5

PP3

MetaRNN computational evidence supports a deleterious effect, 0.989

PP5

Variant 1-40281367-A-G is Pathogenic according to our data. Variant chr1-40281367-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 140540.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr1-40281367-A-G is described in Lovd as [Pathogenic]. Variant chr1-40281367-A-G is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ZMPSTE24	NM_005857.5 linkuse as main transcript	c.794A>G	p.Asn265Ser	missense_variant	7/10	ENST00000372759.4
ZMPSTE24	XM_047427582.1 linkuse as main transcript	c.545A>G	p.Asn182Ser	missense_variant	6/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris
ZMPSTE24	ENST00000372759.4 linkuse as main transcript	c.794A>G	p.Asn265Ser	missense_variant	7/10	1	NM_005857.5	P1
ZMPSTE24	ENST00000674703.1 linkuse as main transcript	c.*635A>G		3_prime_UTR_variant, NMD_transcript_variant	8/11
ZMPSTE24	ENST00000675754.1 linkuse as main transcript	c.*536A>G		3_prime_UTR_variant, NMD_transcript_variant	8/11
ZMPSTE24	ENST00000675937.1 linkuse as main transcript	c.*39A>G		3_prime_UTR_variant, NMD_transcript_variant	8/11

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152200

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000119

AC:

AN:

251390

Hom.:

AF XY:

0.0000147

AC XY:

AN XY:

135880

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000264

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000205

AC:

AN:

1461806

Hom.:

Cov.:

AF XY:

0.0000193

AC XY:

AN XY:

727200

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.0000383

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000261

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152200

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74362

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000844

Hom.:

Bravo

AF:

0.00000756

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1Other:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Pathogenic:1Other:1

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Nov 05, 2021	This sequence change replaces asparagine with serine at codon 265 of the ZMPSTE24 protein (p.Asn265Ser). There is a small physicochemical difference between asparagine and serine. For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. Experimental studies have shown that this missense change affects ZMPSTE24 function (PMID: 17152860, 22718200). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Not Available"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Not Available"). ClinVar contains an entry for this variant (Variation ID: 140540). This missense change has been observed in individual(s) with mandibuloacral dysplasia with lipodystrophy (PMID: 15937076, 17152860, 25629449, 30919593). In at least one individual the data is consistent with the variant being in trans (on the opposite chromosome) from a pathogenic variant. This variant is present in population databases (rs281875371, gnomAD 0.003%). -
not provided, no classification provided	literature only	ZMPSTE24 homepage - Leiden Muscular Dystrophy pages	-	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.94

BayesDel_addAF

Uncertain

0.14

BayesDel_noAF

Uncertain

0.020

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.94

Eigen

Pathogenic

0.96

Eigen_PC

Pathogenic

0.89

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Uncertain

0.97

M_CAP

Uncertain

0.24

MetaRNN

Pathogenic

0.99

MetaSVM

Pathogenic

0.96

MutationAssessor

Pathogenic

4.0

MutationTaster

Benign

1.0

PrimateAI

Pathogenic

0.80

PROVEAN

Pathogenic

-4.6

REVEL

Pathogenic

0.85

Sift

Uncertain

0.0040

Sift4G

Pathogenic

0.0

Polyphen

0.91

Vest4

0.93

MutPred

0.98

Gain of disorder (P = 0.0574);

MVP

1.0

MPC

0.63

ClinPred

0.99

GERP RS

5.7

Varity_R

0.84

gMVP

0.78

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.10

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

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