1-40283083-C-T

Variant names:

• chr1-40283083-C-T
• rs10489430
• NM_005857.5:c.954+1556C>T

Variant summary

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

The NM_005857.5(ZMPSTE24):​c.954+1556C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.616 in 152,068 control chromosomes in the GnomAD database, including 31,463 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 0.62 (31463 hom., cov: 32)
• Consequence: ZMPSTE24 NM_005857.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.188
• Publications: 7 publications found

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]

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: Labcorp Genetics (formerly Invitae), Orphanet, Ambry Genetics, ClinGen, Genomics England PanelApp
• 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=-0.96).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.89 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005857.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZMPSTE24	NM_005857.5	MANE Select	c.954+1556C>T		intron	N/A	NP_005848.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZMPSTE24	ENST00000372759.4	TSL:1 MANE Select	c.954+1556C>T		intron	N/A	ENSP00000361845.3	O75844
	ZMPSTE24	ENST00000869004.1		c.954+1556C>T		intron	N/A	ENSP00000539063.1
	ZMPSTE24	ENST00000869005.1		c.954+1556C>T		intron	N/A	ENSP00000539064.1

Frequencies

GnomAD3 genomes AF: 0.616 AC: 93534 AN: 151948 Hom.: 31392 Cov.: 32

Gnomad AFR AF: 0.897

Gnomad AMI AF: 0.392

Gnomad AMR AF: 0.541

Gnomad ASJ AF: 0.405

Gnomad EAS AF: 0.727

Gnomad SAS AF: 0.660

Gnomad FIN AF: 0.543

Gnomad MID AF: 0.453

Gnomad NFE AF: 0.477

Gnomad OTH AF: 0.551

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.616 AC: 93673 AN: 152068 Hom.: 31463 Cov.: 32 AF XY: 0.621 AC XY: 46133 AN XY: 74324

African (AFR) AF: 0.897 AC: 37257 AN: 41516

American (AMR) AF: 0.542 AC: 8271 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.405 AC: 1406 AN: 3472

East Asian (EAS) AF: 0.728 AC: 3765 AN: 5174

South Asian (SAS) AF: 0.659 AC: 3176 AN: 4822

European-Finnish (FIN) AF: 0.543 AC: 5734 AN: 10554

Middle Eastern (MID) AF: 0.456 AC: 134 AN: 294

European-Non Finnish (NFE) AF: 0.477 AC: 32399 AN: 67948

Other (OTH) AF: 0.556 AC: 1174 AN: 2110

Alfa AF: 0.513 Hom.: 85210

Bravo AF: 0.627

Asia WGS AF: 0.719 AC: 2504 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.96
CADD	Benign	0.58
DANN	Benign	0.58
PhyloP100		-0.19
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs10489430; hg19: chr1-40748755; COSMIC: COSV65638976;