rs16827109

chr1-40270145-T-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.627+18T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0982 in 1,613,024 control chromosomes in the GnomAD database, including 8,239 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.090 (716 hom., cov: 32)
  • Exomes 𝑓: 0.099 (7523 hom.)
• Consequence: ZMPSTE24 NM_005857.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3 O:1
• Conservation: PhyloP100: 0.241

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=-0.75).
• BP6: Variant 1-40270145-T-G is Benign according to our data. Variant chr1-40270145-T-G is described in ClinVar as [Benign]. Clinvar id is 140531.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-40270145-T-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.145 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ZMPSTE24	NM_005857.5	c.627+18T>G		intron_variant		ENST00000372759.4
ZMPSTE24	XM_047427582.1	c.378+18T>G		intron_variant
ZMPSTE24	XM_047427590.1	c.627+18T>G		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ZMPSTE24	ENST00000372759.4	c.627+18T>G		intron_variant		1	NM_005857.5	P1
ZMPSTE24	ENST00000674703.1	c.*468+18T>G		intron_variant, NMD_transcript_variant
ZMPSTE24	ENST00000675754.1	c.*369+18T>G		intron_variant, NMD_transcript_variant
ZMPSTE24	ENST00000675937.1	c.627+18T>G		intron_variant, NMD_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.0901 AC: 13718 AN: 152170 Hom.: 714 Cov.: 32

Gnomad AFR AF: 0.0647

Gnomad AMI AF: 0.0428

Gnomad AMR AF: 0.135

Gnomad ASJ AF: 0.0565

Gnomad EAS AF: 0.153

Gnomad SAS AF: 0.153

Gnomad FIN AF: 0.0925

Gnomad MID AF: 0.0918

Gnomad NFE AF: 0.0884

Gnomad OTH AF: 0.0833

GnomAD3 exomes AF: 0.107 AC: 26839 AN: 251184 Hom.: 1622 AF XY: 0.108 AC XY: 14600 AN XY: 135776

Gnomad AFR exome AF: 0.0627

Gnomad AMR exome AF: 0.145

Gnomad ASJ exome AF: 0.0635

Gnomad EAS exome AF: 0.162

Gnomad SAS exome AF: 0.147

Gnomad FIN exome AF: 0.0894

Gnomad NFE exome AF: 0.0892

Gnomad OTH exome AF: 0.101

GnomAD4 exome AF: 0.0990 AC: 144638 AN: 1460736 Hom.: 7523 Cov.: 32 AF XY: 0.0995 AC XY: 72322 AN XY: 726764

Gnomad4 AFR exome AF: 0.0616

Gnomad4 AMR exome AF: 0.140

Gnomad4 ASJ exome AF: 0.0598

Gnomad4 EAS exome AF: 0.132

Gnomad4 SAS exome AF: 0.147

Gnomad4 FIN exome AF: 0.0899

Gnomad4 NFE exome AF: 0.0952

Gnomad4 OTH exome AF: 0.0989

GnomAD4 genome AF: 0.0902 AC: 13738 AN: 152288 Hom.: 716 Cov.: 32 AF XY: 0.0923 AC XY: 6874 AN XY: 74466

Gnomad4 AFR AF: 0.0645

Gnomad4 AMR AF: 0.136

Gnomad4 ASJ AF: 0.0565

Gnomad4 EAS AF: 0.153

Gnomad4 SAS AF: 0.154

Gnomad4 FIN AF: 0.0925

Gnomad4 NFE AF: 0.0884

Gnomad4 OTH AF: 0.0866

Alfa AF: 0.0878 Hom.: 623

Bravo AF: 0.0918

Asia WGS AF: 0.131 AC: 456 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2 Other:1

Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 04, 2019	- -
not provided, no classification provided	literature only	ZMPSTE24 homepage - Leiden Muscular Dystrophy pages	-	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.75
Cadd	Benign	9.0
Dann	Benign	0.78
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.2

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: rs16827109; hg19: chr1-40735817; COSMIC: COSV65638901; COSMIC: COSV65638901;