1-40257946-G-A

Variant names:

• chr1-40257946-G-A
• rs3765483
• ENST00000567508.3:n.49C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000567508.3(ZMPSTE24-DT):​n.49C>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 ENST00000567508.3 non_coding_transcript_exon
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2 O:1
• Conservation: PhyloP100: -0.172
• Publications: 11 publications found

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]

ZMPSTE24 Gene-Disease associations (from GenCC):

• lethal restrictive dermopathy

  Inheritance: AR, AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, Ambry Genetics, Orphanet
• mandibuloacral dysplasia with type B lipodystrophy

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: Genomics England PanelApp, Ambry Genetics, ClinGen, Labcorp Genetics (formerly Invitae), Orphanet
• restrictive dermopathy 1

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
• Hutchinson-Gilford progeria syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -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.
• 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	ENST00000567508.3	n.49C>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

African (AFR) AF: 0.0986 AC: 656 AN: 6652

American (AMR) AF: 0.122 AC: 1065 AN: 8722

Ashkenazi Jewish (ASJ) AF: 0.0559 AC: 330 AN: 5900

East Asian (EAS) AF: 0.127 AC: 1386 AN: 10902

South Asian (SAS) AF: 0.139 AC: 3758 AN: 27110

European-Finnish (FIN) AF: 0.0850 AC: 888 AN: 10444

Middle Eastern (MID) AF: 0.0671 AC: 55 AN: 820

European-Non Finnish (NFE) AF: 0.0822 AC: 9555 AN: 116212

Other (OTH) AF: 0.0894 AC: 1007 AN: 11260

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

African (AFR) AF: 0.111 AC: 4616 AN: 41550

American (AMR) AF: 0.136 AC: 2074 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.0562 AC: 195 AN: 3470

East Asian (EAS) AF: 0.153 AC: 792 AN: 5176

South Asian (SAS) AF: 0.154 AC: 744 AN: 4824

European-Finnish (FIN) AF: 0.0928 AC: 984 AN: 10600

Middle Eastern (MID) AF: 0.0986 AC: 29 AN: 294

European-Non Finnish (NFE) AF: 0.0894 AC: 6077 AN: 68012

Other (OTH) AF: 0.0983 AC: 208 AN: 2116

Alfa AF: 0.0942 Hom.: 874

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

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

-

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
PhyloP100		-0.17
PromoterAI		-0.11	Neutral

Splicing

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

Other links and lift over

dbSNP: rs3765483; hg19: chr1-40723618;