rs75470795

Positions:

• chr1-40268618-A-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_005857.5(ZMPSTE24):​c.474+83A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0267 in 903,466 control chromosomes in the GnomAD database, including 416 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.022 (50 hom., cov: 32)
  • Exomes 𝑓: 0.028 (366 hom.)
• Consequence: ZMPSTE24 NM_005857.5 intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1 O:1
• Conservation: PhyloP100: 0.0940

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=-0.78).
• BP6: Variant 1-40268618-A-C is Benign according to our data. Variant chr1-40268618-A-C is described in ClinVar as [Likely_benign]. Clinvar id is 140527.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr1-40268618-A-C is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0218 (3320/152330) while in subpopulation NFE AF= 0.0328 (2230/68042). AF 95% confidence interval is 0.0316. There are 50 homozygotes in gnomad4. There are 1606 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 50 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ZMPSTE24	NM_005857.5	c.474+83A>C		intron_variant		ENST00000372759.4
ZMPSTE24	XM_047427582.1	c.225+83A>C		intron_variant
ZMPSTE24	XM_047427590.1	c.474+83A>C		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ZMPSTE24	ENST00000372759.4	c.474+83A>C		intron_variant		1	NM_005857.5	P1
ZMPSTE24	ENST00000674703.1	c.*315+83A>C		intron_variant, NMD_transcript_variant
ZMPSTE24	ENST00000675754.1	c.*216+83A>C		intron_variant, NMD_transcript_variant
ZMPSTE24	ENST00000675937.1	c.474+83A>C		intron_variant, NMD_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.0218 AC: 3319 AN: 152212 Hom.: 50 Cov.: 32

Gnomad AFR AF: 0.00591

Gnomad AMI AF: 0.0482

Gnomad AMR AF: 0.00766

Gnomad ASJ AF: 0.00980

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00911

Gnomad FIN AF: 0.0530

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0328

Gnomad OTH AF: 0.0182

GnomAD4 exome AF: 0.0277 AC: 20840 AN: 751136 Hom.: 366 AF XY: 0.0275 AC XY: 10915 AN XY: 396494

Gnomad4 AFR exome AF: 0.00445

Gnomad4 AMR exome AF: 0.00876

Gnomad4 ASJ exome AF: 0.0112

Gnomad4 EAS exome AF: 0.0000288

Gnomad4 SAS exome AF: 0.0131

Gnomad4 FIN exome AF: 0.0499

Gnomad4 NFE exome AF: 0.0327

Gnomad4 OTH exome AF: 0.0225

GnomAD4 genome AF: 0.0218 AC: 3320 AN: 152330 Hom.: 50 Cov.: 32 AF XY: 0.0216 AC XY: 1606 AN XY: 74494

Gnomad4 AFR AF: 0.00589

Gnomad4 AMR AF: 0.00765

Gnomad4 ASJ AF: 0.00980

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00912

Gnomad4 FIN AF: 0.0530

Gnomad4 NFE AF: 0.0328

Gnomad4 OTH AF: 0.0180

Alfa AF: 0.0282 Hom.: 10

Bravo AF: 0.0179

Asia WGS AF: 0.00866 AC: 30 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:1 Other:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1 Other:1

not provided, no classification provided	literature only	ZMPSTE24 homepage - Leiden Muscular Dystrophy pages	-	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 06, 2020	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	8.8
DANN	Benign	0.85

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs75470795; hg19: chr1-40734290; COSMIC: COSV65639256; COSMIC: COSV65639256;