rs10489432

Positions:

• chr1-40293559-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_005857.5(ZMPSTE24):​c.*890A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0799 in 152,290 control chromosomes in the GnomAD database, including 632 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.080 (632 hom., cov: 32)
  • Failed GnomAD Quality Control
• Consequence: ZMPSTE24 NM_005857.5 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3 O:1
• Conservation: PhyloP100: -1.11

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 1-40293559-A-G is Benign according to our data. Variant chr1-40293559-A-G is described in ClinVar as [Benign]. Clinvar id is 140501.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-40293559-A-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.216 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ZMPSTE24	NM_005857.5	c.*890A>G		3_prime_UTR_variant	10/10	ENST00000372759.4	NP_005848.2
ZMPSTE24	XM_047427582.1	c.*890A>G		3_prime_UTR_variant	9/9		XP_047283538.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ZMPSTE24	ENST00000372759.4	c.*890A>G		3_prime_UTR_variant	10/10	1	NM_005857.5	ENSP00000361845.3

Frequencies

GnomAD3 genomes AF: 0.0798 AC: 12146 AN: 152172 Hom.: 627 Cov.: 32

Gnomad AFR AF: 0.0624

Gnomad AMI AF: 0.110

Gnomad AMR AF: 0.113

Gnomad ASJ AF: 0.0833

Gnomad EAS AF: 0.226

Gnomad SAS AF: 0.197

Gnomad FIN AF: 0.0524

Gnomad MID AF: 0.0759

Gnomad NFE AF: 0.0673

Gnomad OTH AF: 0.0804

GnomAD4 exome Data not reliable, filtered out with message: AC0 AC: 0 AN: 0 Hom.: 0 Cov.: 0 AC XY: 0 AN XY: 0

GnomAD4 genome AF: 0.0799 AC: 12163 AN: 152290 Hom.: 632 Cov.: 32 AF XY: 0.0819 AC XY: 6097 AN XY: 74458

Gnomad4 AFR AF: 0.0624

Gnomad4 AMR AF: 0.113

Gnomad4 ASJ AF: 0.0833

Gnomad4 EAS AF: 0.227

Gnomad4 SAS AF: 0.197

Gnomad4 FIN AF: 0.0524

Gnomad4 NFE AF: 0.0673

Gnomad4 OTH AF: 0.0795

Alfa AF: 0.0747 Hom.: 814

Bravo AF: 0.0844

Asia WGS AF: 0.213 AC: 741 AN: 3476

ClinVar

Significance: Benign

Submissions summary: Benign:3 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1 Other:1

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
not provided, no classification provided	literature only	ZMPSTE24 homepage - Leiden Muscular Dystrophy pages	-	- -

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	-0.84
CADD	Benign	0.037
DANN	Benign	0.41

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: rs10489432; hg19: chr1-40759231;