rs2076697

Variant names:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_005857.5(ZMPSTE24):c.651T>C(p.Asp217Asp) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0846 in 1,613,256 control chromosomes in the GnomAD database, including 7,390 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.080 ( 652 hom., cov: 32)

Exomes 𝑓: 0.085 ( 6738 hom. )

Consequence

ZMPSTE24
NM_005857.5 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:8O:1

Conservation

PhyloP100: 1.17

Publications

18 publications found

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 Gene-Disease associations (from GenCC):

lethal restrictive dermopathy
Inheritance: AR, AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, Ambry Genetics, Orphanet
mandibuloacral dysplasia with type B lipodystrophy
Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: Genomics England PanelApp, Ambry Genetics, ClinGen, Labcorp Genetics (formerly Invitae), Orphanet
restrictive dermopathy 1
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
Hutchinson-Gilford progeria syndrome
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ZMPSTE24 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.52).

BP6

Variant 1-40271917-T-C is Benign according to our data. Variant chr1-40271917-T-C is described in ClinVar as Benign. ClinVar VariationId is 95316.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=1.17 with no splicing effect.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.218 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
ZMPSTE24	NM_005857.5 link	c.651T>C	p.Asp217Asp	synonymous_variant	Exon 6 of 10	ENST00000372759.4	NP_005848.2
ZMPSTE24	XM_047427582.1 link	c.402T>C	p.Asp134Asp	synonymous_variant	Exon 5 of 9		XP_047283538.1
ZMPSTE24	XM_047427590.1 link	c.651T>C	p.Asp217Asp	synonymous_variant	Exon 6 of 7		XP_047283546.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ZMPSTE24	ENST00000372759.4 link	c.651T>C	p.Asp217Asp	synonymous_variant	Exon 6 of 10	1	NM_005857.5	ENSP00000361845.3

Frequencies

GnomAD3 genomes

AF:

0.0804

AC:

12228

AN:

152172

Hom.:

648

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0598

Gnomad AMI

AF:

0.110

Gnomad AMR

AF:

0.114

Gnomad ASJ

AF:

0.0830

Gnomad EAS

AF:

0.229

Gnomad SAS

AF:

0.199

Gnomad FIN

AF:

0.0619

Gnomad MID

AF:

0.0791

Gnomad NFE

AF:

0.0679

Gnomad OTH

AF:

0.0837

GnomAD2 exomes

AF:

0.108

AC:

27106

AN:

251210

AF XY:

0.110

show subpopulations

Gnomad AFR exome

AF:

0.0627

Gnomad AMR exome

AF:

0.150

Gnomad ASJ exome

AF:

0.0806

Gnomad EAS exome

AF:

0.236

Gnomad FIN exome

AF:

0.0658

Gnomad NFE exome

AF:

0.0690

Gnomad OTH exome

AF:

0.0920

GnomAD4 exome

AF:

0.0850

AC:

124166

AN:

1460966

Hom.:

6738

Cov.:

AF XY:

0.0884

AC XY:

64244

AN XY:

726792

show subpopulations

African (AFR)

AF:

0.0592

AC:

1981

AN:

33464

American (AMR)

AF:

0.146

AC:

6544

AN:

44700

Ashkenazi Jewish (ASJ)

AF:

0.0818

AC:

2137

AN:

26114

East Asian (EAS)

AF:

0.236

AC:

9338

AN:

39590

South Asian (SAS)

AF:

0.192

AC:

16574

AN:

86184

European-Finnish (FIN)

AF:

0.0637

AC:

3402

AN:

53378

Middle Eastern (MID)

AF:

0.0751

AC:

433

AN:

5764

European-Non Finnish (NFE)

AF:

0.0703

AC:

78139

AN:

1111424

Other (OTH)

AF:

0.0931

AC:

5618

AN:

60348

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.466

Heterozygous variant carriers

5246

10491

15737

20982

26228

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

3178

6356

9534

12712

15890

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0804

AC:

12243

AN:

152290

Hom.:

652

Cov.:

AF XY:

0.0822

AC XY:

6122

AN XY:

74476

show subpopulations

African (AFR)

AF:

0.0598

AC:

2487

AN:

41574

American (AMR)

AF:

0.114

AC:

1745

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.0830

AC:

288

AN:

3470

East Asian (EAS)

AF:

0.229

AC:

1185

AN:

5176

South Asian (SAS)

AF:

0.199

AC:

960

AN:

4830

European-Finnish (FIN)

AF:

0.0619

AC:

658

AN:

10624

Middle Eastern (MID)

AF:

0.0816

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0679

AC:

4620

AN:

68014

Other (OTH)

AF:

0.0833

AC:

176

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

560

1120

1679

2239

2799

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

148

296

444

592

740

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0754

Hom.:

692

Bravo

AF:

0.0833

Asia WGS

AF:

0.217

AC:

752

AN:

3472

EpiCase

AF:

0.0677

EpiControl

AF:

0.0683

ClinVar

Significance: Benign

Submissions summary: Benign:8Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3Other:1

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

ZMPSTE24 homepage - Leiden Muscular Dystrophy pages

Significance:not provided

Review Status:no classification provided

Collection Method:literature only

- -

Nov 18, 2019

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:3

Jul 23, 2013

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Genetic Services Laboratory, University of Chicago

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -

Mandibuloacral dysplasia with type B lipodystrophy

Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Lethal tight skin contracture syndrome

Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.52

CADD

Benign

(source)

DANN

Benign

0.56

PhyloP100

1.2

Mutation Taster

=92/8

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over