NM_005857.5:c.1085dupT

Variant names:

• chr1-40290870-G-GT
• rs137854889
• NM_005857.5:c.1085dupT

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PVS1 PP5_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 (★★). 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
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:20 O:1
• Conservation: PhyloP100: 0.923
• Publications: 34 publications found

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

ACMG classification

Our verdict: Pathogenic. The variant received 16 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• 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

Sel.	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: 49 AN: 151082 Hom.: 0 Cov.: 31

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: 85 AN: 242964 AF XY: 0.000373

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.: 0 Cov.: 31 AF XY: 0.000447 AC XY: 322 AN XY: 721138

African (AFR) AF: 0.000151 AC: 5 AN: 33136

American (AMR) AF: 0.000226 AC: 10 AN: 44286

Ashkenazi Jewish (ASJ) AF: 0.000116 AC: 3 AN: 25870

East Asian (EAS) AF: 0.000179 AC: 7 AN: 39204

South Asian (SAS) AF: 0.000210 AC: 18 AN: 85788

European-Finnish (FIN) AF: 0.0000947 AC: 5 AN: 52822

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5734

European-Non Finnish (NFE) AF: 0.000525 AC: 579 AN: 1102772

Other (OTH) AF: 0.000402 AC: 24 AN: 59714

GnomAD4 genome AF: 0.000324 AC: 49 AN: 151082 Hom.: 0 Cov.: 31 AF XY: 0.000339 AC XY: 25 AN XY: 73724

African (AFR) AF: 0.0000974 AC: 4 AN: 41074

American (AMR) AF: 0.0000661 AC: 1 AN: 15134

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.000194 AC: 1 AN: 5162

South Asian (SAS) AF: 0.000419 AC: 2 AN: 4770

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10440

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000605 AC: 41 AN: 67740

Other (OTH) AF: 0.00 AC: 0 AN: 2070

Alfa AF: 0.000622 Hom.: 0

Bravo AF: 0.000302

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
7	-	-	not provided (8)
6	-	-	Lethal tight skin contracture syndrome (6)
3	-	-	Mandibuloacral dysplasia with type B lipodystrophy (3)
2	-	-	Restrictive dermopathy 1 (2)
1	-	-	Lethal tight skin contracture syndrome;C1837756:Mandibuloacral dysplasia with type B lipodystrophy (1)
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)

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

Other links and lift over

dbSNP: rs137854889; hg19: chr1-40756542; COSMIC: COSV65638686;