rs2076697

Positions:

• chr1-40271917-T-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_005857.5(ZMPSTE24):​c.651T>C​(p.Asp217=) 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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8 O:1
• Conservation: PhyloP100: 1.17

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]

ACMG classification

Verdict is Benign. Variant got -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 id is 95316.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-40271917-T-C is described in Lovd as [Benign].
• 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/exons	MANE	Protein	UniProt
ZMPSTE24	NM_005857.5	c.651T>C	p.Asp217=	synonymous_variant	6/10	ENST00000372759.4	NP_005848.2
ZMPSTE24	XM_047427582.1	c.402T>C	p.Asp134=	synonymous_variant	5/9		XP_047283538.1
ZMPSTE24	XM_047427590.1	c.651T>C	p.Asp217=	synonymous_variant	6/7		XP_047283546.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ZMPSTE24	ENST00000372759.4	c.651T>C	p.Asp217=	synonymous_variant	6/10	1	NM_005857.5	ENSP00000361845	P1
ZMPSTE24	ENST00000675937.1	c.651T>C	p.Asp217=	synonymous_variant, NMD_transcript_variant	6/11			ENSP00000502683
ZMPSTE24	ENST00000674703.1	c.*492T>C		3_prime_UTR_variant, NMD_transcript_variant	7/11			ENSP00000501674
ZMPSTE24	ENST00000675754.1	c.*393T>C		3_prime_UTR_variant, NMD_transcript_variant	7/11			ENSP00000502555

Frequencies

GnomAD3 genomes AF: 0.0804 AC: 12228 AN: 152172 Hom.: 648 Cov.: 32

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

GnomAD3 exomes AF: 0.108 AC: 27106 AN: 251210 Hom.: 1953 AF XY: 0.110 AC XY: 14998 AN XY: 135814

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 SAS exome AF: 0.194

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.: 32 AF XY: 0.0884 AC XY: 64244 AN XY: 726792

Gnomad4 AFR exome AF: 0.0592

Gnomad4 AMR exome AF: 0.146

Gnomad4 ASJ exome AF: 0.0818

Gnomad4 EAS exome AF: 0.236

Gnomad4 SAS exome AF: 0.192

Gnomad4 FIN exome AF: 0.0637

Gnomad4 NFE exome AF: 0.0703

Gnomad4 OTH exome AF: 0.0931

GnomAD4 genome AF: 0.0804 AC: 12243 AN: 152290 Hom.: 652 Cov.: 32 AF XY: 0.0822 AC XY: 6122 AN XY: 74476

Gnomad4 AFR AF: 0.0598

Gnomad4 AMR AF: 0.114

Gnomad4 ASJ AF: 0.0830

Gnomad4 EAS AF: 0.229

Gnomad4 SAS AF: 0.199

Gnomad4 FIN AF: 0.0619

Gnomad4 NFE AF: 0.0679

Gnomad4 OTH AF: 0.0833

Alfa AF: 0.0742 Hom.: 449

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:8 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3 Other:1

Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 18, 2019	- -
not provided, no classification provided	literature only	ZMPSTE24 homepage - Leiden Muscular Dystrophy pages	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 30, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 23, 2013	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	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

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

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

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.52
CADD	Benign	11
DANN	Benign	0.56

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

LitVar

Other links and lift over

dbSNP: rs2076697; hg19: chr1-40737589; COSMIC: COSV65638821; COSMIC: COSV65638821;