1-40267986-A-G

Position:

• chr1-40267986-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.357+114A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.246 in 888,632 control chromosomes in the GnomAD database, including 27,870 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.25 (4981 hom., cov: 32)
  • Exomes 𝑓: 0.25 (22889 hom.)
• Consequence: ZMPSTE24 NM_005857.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2 O:1
• Conservation: PhyloP100: -1.13

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=-0.85).
• BP6: Variant 1-40267986-A-G is Benign according to our data. Variant chr1-40267986-A-G is described in ClinVar as [Benign]. Clinvar id is 140525.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-40267986-A-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.262 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ZMPSTE24	NM_005857.5	c.357+114A>G		intron_variant		ENST00000372759.4	NP_005848.2
ZMPSTE24	XM_047427582.1	c.108+114A>G		intron_variant			XP_047283538.1
ZMPSTE24	XM_047427590.1	c.357+114A>G		intron_variant			XP_047283546.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ZMPSTE24	ENST00000372759.4	c.357+114A>G		intron_variant		1	NM_005857.5	ENSP00000361845.3
ZMPSTE24	ENST00000674703.1	n.*198+114A>G		intron_variant				ENSP00000501674.1
ZMPSTE24	ENST00000675754.1	n.*99+114A>G		intron_variant				ENSP00000502555.1
ZMPSTE24	ENST00000675937.1	n.357+114A>G		intron_variant				ENSP00000502683.1

Frequencies

GnomAD3 genomes AF: 0.252 AC: 38365 AN: 152038 Hom.: 4981 Cov.: 32

Gnomad AFR AF: 0.267

Gnomad AMI AF: 0.130

Gnomad AMR AF: 0.180

Gnomad ASJ AF: 0.222

Gnomad EAS AF: 0.240

Gnomad SAS AF: 0.179

Gnomad FIN AF: 0.294

Gnomad MID AF: 0.184

Gnomad NFE AF: 0.263

Gnomad OTH AF: 0.240

GnomAD4 exome AF: 0.245 AC: 180441 AN: 736474 Hom.: 22889 AF XY: 0.241 AC XY: 94798 AN XY: 393116

Gnomad4 AFR exome AF: 0.263

Gnomad4 AMR exome AF: 0.181

Gnomad4 ASJ exome AF: 0.223

Gnomad4 EAS exome AF: 0.248

Gnomad4 SAS exome AF: 0.178

Gnomad4 FIN exome AF: 0.298

Gnomad4 NFE exome AF: 0.257

Gnomad4 OTH exome AF: 0.240

GnomAD4 genome AF: 0.252 AC: 38363 AN: 152158 Hom.: 4981 Cov.: 32 AF XY: 0.251 AC XY: 18700 AN XY: 74368

Gnomad4 AFR AF: 0.266

Gnomad4 AMR AF: 0.180

Gnomad4 ASJ AF: 0.222

Gnomad4 EAS AF: 0.240

Gnomad4 SAS AF: 0.178

Gnomad4 FIN AF: 0.294

Gnomad4 NFE AF: 0.263

Gnomad4 OTH AF: 0.239

Alfa AF: 0.205 Hom.: 795

Bravo AF: 0.244

Asia WGS AF: 0.217 AC: 754 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2 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	Nov 13, 2018	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
not provided, no classification provided	literature only	ZMPSTE24 homepage - Leiden Muscular Dystrophy pages	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	0.95
DANN	Benign	0.73

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: rs7516571; hg19: chr1-40733658; COSMIC: COSV65638895; COSMIC: COSV65638895;