1-40290870-GT-GTTT

Variant names:

• chr1-40290870-G-GTT
• rs137854889
• NM_005857.5:c.1084_1085dupTT

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PVS1 PM2

The NM_005857.5(ZMPSTE24):​c.1084_1085dupTT​(p.Leu362PhefsTer6) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to 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: not found (cov: 31)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: ZMPSTE24 NM_005857.5 frameshift
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.923
• Publications: 0 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 10 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

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.1084_1085dupTT	p.Leu362PhefsTer6	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.1084_1085dupTT	p.Leu362PhefsTer6	frameshift	Exon 9 of 10	ENSP00000361845.3	O75844
	ZMPSTE24	ENST00000869005.1		c.979_980dupTT	p.Leu327PhefsTer6	frameshift	Exon 8 of 9	ENSP00000539064.1
	ZMPSTE24	ENST00000869008.1		c.937_938dupTT	p.Leu313PhefsTer6	frameshift	Exon 8 of 9	ENSP00000539067.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1453040 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 722874

African (AFR) AF: 0.00 AC: 0 AN: 33236

American (AMR) AF: 0.00 AC: 0 AN: 44374

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25920

East Asian (EAS) AF: 0.00 AC: 0 AN: 39312

South Asian (SAS) AF: 0.00 AC: 0 AN: 85906

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52990

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5744

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1105648

Other (OTH) AF: 0.00 AC: 0 AN: 59910

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.92

Splicing

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

Other links and lift over

dbSNP: rs137854889; hg19: chr1-40756542;