1-40290870-GT-GTT

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 20 ACMG points: 20P and 0B. PVS1PS3PP5_Very_Strong

The NM_005857.5(ZMPSTE24):c.1085dupT(p.Leu362PhefsTer19) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000437 in 1,600,408 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV001168548: Published functional studies demonstrate a damaging effect with no proteolytic activity observed (PMID:22718200)" and additional evidence is available in ClinVar. Synonymous variant affecting the same amino acid position (i.e. L362L) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.00032 ( 0 hom., cov: 31)

Exomes 𝑓: 0.00045 ( 0 hom. )

Consequence

ZMPSTE24
NM_005857.5 frameshift

Scores

Not classified

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:20O:1

Conservation

PhyloP100: 0.923

Publications

34 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: Labcorp Genetics (formerly Invitae), Orphanet, Ambry Genetics, ClinGen, Genomics England PanelApp
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: Pathogenic. The variant received 20 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PS3

PS3 evidence extracted from ClinVar submissions: SCV001168548: Published functional studies demonstrate a damaging effect with no proteolytic activity observed (PMID: 22718200); SCV000357433: Yeast complementation assays demonstrated that the p.Leu362PhefsTer19 variant protein, unlike wild type, was unable to rescue a growth arrest phenotype and results in only 1% of the wild type protein activity (Barrowman et al. 2012).

PP5

Variant 1-40290870-G-GT is Pathogenic according to our data. Variant chr1-40290870-G-GT is described in ClinVar as Pathogenic. ClinVar VariationId is 4271.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005857.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZMPSTE24	NM_005857.5	MANE Select	c.1085dupT	p.Leu362PhefsTer19	frameshift	Exon 9 of 10	NP_005848.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ZMPSTE24	ENST00000372759.4	TSL:1 MANE Select	c.1085dupT	p.Leu362PhefsTer19	frameshift	Exon 9 of 10	ENSP00000361845.3	O75844
ZMPSTE24	ENST00000869005.1		c.980dupT	p.Leu327PhefsTer19	frameshift	Exon 8 of 9	ENSP00000539064.1
ZMPSTE24	ENST00000869008.1		c.938dupT	p.Leu313PhefsTer19	frameshift	Exon 8 of 9	ENSP00000539067.1

Frequencies

GnomAD3 genomes

AF:

0.000324

AC:

AN:

151082

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000974

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000661

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000194

Gnomad SAS

AF:

0.000419

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000605

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000350

AC:

AN:

242964

AF XY:

0.000373

show subpopulations

Gnomad AFR exome

AF:

0.000126

Gnomad AMR exome

AF:

0.000212

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000112

Gnomad FIN exome

AF:

0.0000478

Gnomad NFE exome

AF:

0.000525

Gnomad OTH exome

AF:

0.000507

GnomAD4 exome

AF:

0.000449

AC:

651

AN:

1449326

Hom.:

Cov.:

AF XY:

0.000447

AC XY:

322

AN XY:

721138

show subpopulations

African (AFR)

AF:

0.000151

AC:

AN:

33136

American (AMR)

AF:

0.000226

AC:

AN:

44286

Ashkenazi Jewish (ASJ)

AF:

0.000116

AC:

AN:

25870

East Asian (EAS)

AF:

0.000179

AC:

AN:

39204

South Asian (SAS)

AF:

0.000210

AC:

AN:

85788

European-Finnish (FIN)

AF:

0.0000947

AC:

AN:

52822

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5734

European-Non Finnish (NFE)

AF:

0.000525

AC:

579

AN:

1102772

Other (OTH)

AF:

0.000402

AC:

AN:

59714

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.424

Heterozygous variant carriers

108

144

180

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

120

<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:

0.000324

AC:

AN:

151082

Hom.:

Cov.:

AF XY:

0.000339

AC XY:

AN XY:

73724

show subpopulations

African (AFR)

AF:

0.0000974

AC:

AN:

41074

American (AMR)

AF:

0.0000661

AC:

AN:

15134

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3466

East Asian (EAS)

AF:

0.000194

AC:

AN:

5162

South Asian (SAS)

AF:

0.000419

AC:

AN:

4770

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10440

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.000605

AC:

AN:

67740

Other (OTH)

AF:

0.00

AC:

AN:

2070

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.492

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.000622

Hom.:

Bravo

AF:

0.000302

ClinVar

ClinVar submissions

Significance:Pathogenic

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (8)

Lethal tight skin contracture syndrome (6)

Mandibuloacral dysplasia with type B lipodystrophy (3)

Restrictive dermopathy 1 (2)

Lethal tight skin contracture syndrome;C1837756:Mandibuloacral dysplasia with type B lipodystrophy (1)

ZMPSTE24-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

0.92

Mutation Taster

=8/192

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.13

Details are displayed if max score is > 0.2

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over