1-40282247-A-C

Variant names:

• chr1-40282247-A-C
• rs6691598
• NM_005857.5:c.954+720A>C

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+720A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.521 in 152,062 control chromosomes in the GnomAD database, including 22,065 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 0.52 (22065 hom., cov: 33)
• Consequence: ZMPSTE24 NM_005857.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.313
• Publications: 6 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: 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=-0.85).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.714 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZMPSTE24	NM_005857.5	MANE Select	c.954+720A>C		intron	N/A	NP_005848.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZMPSTE24	ENST00000372759.4	TSL:1 MANE Select	c.954+720A>C		intron	N/A	ENSP00000361845.3
	ZMPSTE24	ENST00000674703.1		n.*795+720A>C		intron	N/A	ENSP00000501674.1
	ZMPSTE24	ENST00000675754.1		n.*696+720A>C		intron	N/A	ENSP00000502555.1

Frequencies

GnomAD3 genomes AF: 0.521 AC: 79090 AN: 151944 Hom.: 22024 Cov.: 33

Gnomad AFR AF: 0.721

Gnomad AMI AF: 0.282

Gnomad AMR AF: 0.472

Gnomad ASJ AF: 0.357

Gnomad EAS AF: 0.655

Gnomad SAS AF: 0.556

Gnomad FIN AF: 0.445

Gnomad MID AF: 0.382

Gnomad NFE AF: 0.422

Gnomad OTH AF: 0.475

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

GnomAD4 genome AF: 0.521 AC: 79193 AN: 152062 Hom.: 22065 Cov.: 33 AF XY: 0.523 AC XY: 38836 AN XY: 74326

African (AFR) AF: 0.721 AC: 29903 AN: 41498

American (AMR) AF: 0.473 AC: 7222 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.357 AC: 1238 AN: 3470

East Asian (EAS) AF: 0.655 AC: 3395 AN: 5182

South Asian (SAS) AF: 0.554 AC: 2673 AN: 4822

European-Finnish (FIN) AF: 0.445 AC: 4700 AN: 10554

Middle Eastern (MID) AF: 0.377 AC: 110 AN: 292

European-Non Finnish (NFE) AF: 0.422 AC: 28687 AN: 67958

Other (OTH) AF: 0.480 AC: 1008 AN: 2100

Alfa AF: 0.464 Hom.: 16318

Bravo AF: 0.532

Asia WGS AF: 0.634 AC: 2209 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	7.3
DANN	Benign	0.82
PhyloP100		-0.31
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: rs6691598; hg19: chr1-40747919; COSMIC: COSV65638971;