1-40257972-C-T

Variant names:

• chr1-40257972-C-T
• rs77936656
• ENST00000567508.3:n.23G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000567508.3(ZMPSTE24-DT):​n.23G>A 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 0.00816 in 446,042 control chromosomes in the GnomAD database, including 100 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.019 (83 hom., cov: 32)
  • Exomes 𝑓: 0.0026 (17 hom.)
• Consequence: ZMPSTE24-DT ENST00000567508.3 non_coding_transcript_exon
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.538
• Publications: 1 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0643 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.23G>A		non_coding_transcript_exon_variant	Exon 1 of 1	6
ZMPSTE24	ENST00000674703.1	n.-300C>T		upstream_gene_variant				ENSP00000501674.1
ZMPSTE24	ENST00000675937.1	n.-300C>T		upstream_gene_variant				ENSP00000502683.1

Frequencies

GnomAD3 genomes AF: 0.0189 AC: 2873 AN: 152192 Hom.: 82 Cov.: 32

Gnomad AFR AF: 0.0664

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00582

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000103

Gnomad OTH AF: 0.0120

GnomAD4 exome AF: 0.00259 AC: 760 AN: 293732 Hom.: 17 Cov.: 3 AF XY: 0.00221 AC XY: 340 AN XY: 153900

African (AFR) AF: 0.0668 AC: 604 AN: 9036

American (AMR) AF: 0.00365 AC: 47 AN: 12890

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 8998

East Asian (EAS) AF: 0.00 AC: 0 AN: 17926

South Asian (SAS) AF: 0.0000547 AC: 2 AN: 36556

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 16382

Middle Eastern (MID) AF: 0.00163 AC: 2 AN: 1226

European-Non Finnish (NFE) AF: 0.000161 AC: 28 AN: 173868

Other (OTH) AF: 0.00457 AC: 77 AN: 16850

GnomAD4 genome AF: 0.0189 AC: 2881 AN: 152310 Hom.: 83 Cov.: 32 AF XY: 0.0181 AC XY: 1346 AN XY: 74478

African (AFR) AF: 0.0664 AC: 2760 AN: 41560

American (AMR) AF: 0.00575 AC: 88 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000103 AC: 7 AN: 68034

Other (OTH) AF: 0.0118 AC: 25 AN: 2112

Alfa AF: 0.0139 Hom.: 7

Bravo AF: 0.0220

Asia WGS AF: 0.00318 AC: 11 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Nov 15, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	9.5
DANN	Benign	0.74
PhyloP100		0.54
PromoterAI		0.024	Neutral

Splicing

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

Other links and lift over

dbSNP: rs77936656; hg19: chr1-40723644;