rs10489431

chr1-40293392-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_005857.5(ZMPSTE24):c.*723C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0805 in 151,602 control chromosomes in the GnomAD database, including 629 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.080 (629 hom., cov: 32)
  • Exomes 𝑓: 0.060 (0 hom.)
• Consequence: ZMPSTE24 NM_005857.5 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:2 O:1
• Conservation: PhyloP100: -0.548

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 1-40293392-C-T is Benign according to our data. Variant chr1-40293392-C-T is described in ClinVar as [Benign]. Clinvar id is 140500.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr1-40293392-C-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.215 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ZMPSTE24	NM_005857.5	c.*723C>T		3_prime_UTR_variant	10/10	ENST00000372759.4
ZMPSTE24	XM_047427582.1	c.*723C>T		3_prime_UTR_variant	9/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ZMPSTE24	ENST00000372759.4	c.*723C>T		3_prime_UTR_variant	10/10	1	NM_005857.5	P1
ZMPSTE24	ENST00000674703.1	c.*1992C>T		3_prime_UTR_variant, NMD_transcript_variant	11/11
ZMPSTE24	ENST00000675754.1	c.*1893C>T		3_prime_UTR_variant, NMD_transcript_variant	11/11
ZMPSTE24	ENST00000675937.1	c.*1396C>T		3_prime_UTR_variant, NMD_transcript_variant	11/11

Frequencies

GnomAD3 genomes AF: 0.0804 AC: 12180 AN: 151434 Hom.: 624 Cov.: 32

Gnomad AFR AF: 0.0623

Gnomad AMI AF: 0.110

Gnomad AMR AF: 0.112

Gnomad ASJ AF: 0.0831

Gnomad EAS AF: 0.225

Gnomad SAS AF: 0.196

Gnomad FIN AF: 0.0580

Gnomad MID AF: 0.0759

Gnomad NFE AF: 0.0679

Gnomad OTH AF: 0.0825

GnomAD4 exome AF: 0.0600 AC: 3 AN: 50 Hom.: 0 Cov.: 0 AF XY: 0.107 AC XY: 3 AN XY: 28

Gnomad4 EAS exome AF: 0.500

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0476

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0805 AC: 12198 AN: 151552 Hom.: 629 Cov.: 32 AF XY: 0.0826 AC XY: 6117 AN XY: 74026

Gnomad4 AFR AF: 0.0623

Gnomad4 AMR AF: 0.113

Gnomad4 ASJ AF: 0.0831

Gnomad4 EAS AF: 0.226

Gnomad4 SAS AF: 0.196

Gnomad4 FIN AF: 0.0580

Gnomad4 NFE AF: 0.0680

Gnomad4 OTH AF: 0.0817

Alfa AF: 0.0765 Hom.: 690

Bravo AF: 0.0843

Asia WGS AF: 0.209 AC: 725 AN: 3472

ClinVar

Significance: Benign

Submissions summary: Benign:2 Other:1

Revision: criteria provided, single submitter

Submissions by phenotype

Mandibuloacral dysplasia with type B lipodystrophy Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 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 13, 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. -

not provided Other:1

not provided, no classification provided

literature only

ZMPSTE24 homepage - Leiden Muscular Dystrophy pages

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
Cadd	Benign	0.54
Dann	Benign	0.69
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0

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: rs10489431; hg19: chr1-40759064;