rs3765483

Variant names:

• chr1-40257946-G-A
• rs3765483
• ENST00000567508.2:n.26C>T

Variant summary

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

The ENST00000567508.2(ZMPSTE24-DT):​n.26C>T variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0984 in 350,266 control chromosomes in the GnomAD database, including 1,928 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.10 (902 hom., cov: 32)
  • Exomes 𝑓: 0.094 (1026 hom.)
• Consequence: ZMPSTE24-DT ENST00000567508.2 non_coding_transcript_exon
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2 O:1
• Conservation: PhyloP100: -0.172

Genes affected

ZMPSTE24-DT (HGNC:55402): (ZMPSTE24 divergent transcript)

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=-0.78).
• BP6: Variant 1-40257946-G-A is Benign according to our data. Variant chr1-40257946-G-A is described in ClinVar as [Benign]. Clinvar id is 140505.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-40257946-G-A 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 rank	MANE	Protein	UniProt

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ZMPSTE24-DT	ENST00000567508.2	n.26C>T		non_coding_transcript_exon_variant	Exon 1 of 1	6
ZMPSTE24	ENST00000674703.1	n.-326G>A		upstream_gene_variant				ENSP00000501674.1
ZMPSTE24	ENST00000675937.1	n.-326G>A		upstream_gene_variant				ENSP00000502683.1

Frequencies

GnomAD3 genomes AF: 0.103 AC: 15727 AN: 152126 Hom.: 900 Cov.: 32

Gnomad AFR AF: 0.111

Gnomad AMI AF: 0.0419

Gnomad AMR AF: 0.135

Gnomad ASJ AF: 0.0562

Gnomad EAS AF: 0.153

Gnomad SAS AF: 0.154

Gnomad FIN AF: 0.0928

Gnomad MID AF: 0.0981

Gnomad NFE AF: 0.0893

Gnomad OTH AF: 0.0950

GnomAD4 exome AF: 0.0944 AC: 18700 AN: 198022 Hom.: 1026 Cov.: 3 AF XY: 0.0975 AC XY: 10162 AN XY: 104234

Gnomad4 AFR exome AF: 0.0986

Gnomad4 AMR exome AF: 0.122

Gnomad4 ASJ exome AF: 0.0559

Gnomad4 EAS exome AF: 0.127

Gnomad4 SAS exome AF: 0.139

Gnomad4 FIN exome AF: 0.0850

Gnomad4 NFE exome AF: 0.0822

Gnomad4 OTH exome AF: 0.0894

GnomAD4 genome AF: 0.103 AC: 15757 AN: 152244 Hom.: 902 Cov.: 32 AF XY: 0.105 AC XY: 7797 AN XY: 74440

Gnomad4 AFR AF: 0.111

Gnomad4 AMR AF: 0.136

Gnomad4 ASJ AF: 0.0562

Gnomad4 EAS AF: 0.153

Gnomad4 SAS AF: 0.154

Gnomad4 FIN AF: 0.0928

Gnomad4 NFE AF: 0.0894

Gnomad4 OTH AF: 0.0983

Alfa AF: 0.0919 Hom.: 628

Bravo AF: 0.106

Asia WGS AF: 0.137 AC: 480 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

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Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

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ZMPSTE24 homepage - Leiden Muscular Dystrophy pages

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Sep 04, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	2.0
DANN	Benign	0.86

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs3765483; hg19: chr1-40723618;