chr1-40270082-CTA-C

Variant names:

• chr1-40270082-CTA-C
• rs786205123
• NM_005857.5:c.584_585delAT

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PVS1 PM2 PP5

The NM_005857.5(ZMPSTE24):​c.584_585delAT​(p.Tyr195PhefsTer22) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,526 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (no stars). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: ZMPSTE24 NM_005857.5 frameshift
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 7.63
• Publications: 4 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: 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

ACMG classification

Our verdict: Pathogenic. The variant received 11 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 1-40270082-CTA-C is Pathogenic according to our data. Variant chr1-40270082-CTA-C is described in CliVar as Pathogenic. Clinvar id is 41412.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr1-40270082-CTA-C is described in CliVar as Pathogenic. Clinvar id is 41412.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr1-40270082-CTA-C is described in CliVar as Pathogenic. Clinvar id is 41412.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr1-40270082-CTA-C is described in CliVar as Pathogenic. Clinvar id is 41412.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr1-40270082-CTA-C is described in CliVar as Pathogenic. Clinvar id is 41412.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr1-40270082-CTA-C is described in CliVar as Pathogenic. Clinvar id is 41412.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr1-40270082-CTA-C is described in CliVar as Pathogenic. Clinvar id is 41412.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr1-40270082-CTA-C is described in CliVar as Pathogenic. Clinvar id is 41412.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr1-40270082-CTA-C is described in CliVar as Pathogenic. Clinvar id is 41412.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZMPSTE24	NM_005857.5	c.584_585delAT	p.Tyr195PhefsTer22	frameshift_variant	Exon 5 of 10	ENST00000372759.4	NP_005848.2
ZMPSTE24	XM_047427582.1	c.335_336delAT	p.Tyr112PhefsTer22	frameshift_variant	Exon 4 of 9		XP_047283538.1
ZMPSTE24	XM_047427590.1	c.584_585delAT	p.Tyr195PhefsTer22	frameshift_variant	Exon 5 of 7		XP_047283546.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ZMPSTE24	ENST00000372759.4	c.584_585delAT	p.Tyr195PhefsTer22	frameshift_variant	Exon 5 of 10	1	NM_005857.5	ENSP00000361845.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251146 AF XY: 0.00000737

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000880

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461526 Hom.: 0 AF XY: 0.00000275 AC XY: 2 AN XY: 727052

African (AFR) AF: 0.00 AC: 0 AN: 33466

American (AMR) AF: 0.00 AC: 0 AN: 44688

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26124

East Asian (EAS) AF: 0.00 AC: 0 AN: 39626

South Asian (SAS) AF: 0.00 AC: 0 AN: 86194

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53396

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1111892

Other (OTH) AF: 0.00 AC: 0 AN: 60374

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Lethal tight skin contracture syndrome Pathogenic:1

Feb 01, 2010

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		7.6
Mutation Taster		=1/199	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs786205123; hg19: chr1-40735754;