chr1-40261607-A-G

Variant names:

• chr1-40261607-A-G
• rs7514099
• NM_005857.5:c.270+622A>G

Variant summary

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

The ENST00000372759.4(ZMPSTE24):​c.270+622A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.252 in 152,094 control chromosomes in the GnomAD database, including 4,975 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 0.25 (4975 hom., cov: 32)
• Consequence: ZMPSTE24 ENST00000372759.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.15
• Publications: 4 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=-0.89).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.262 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000372759.4. 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.270+622A>G		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.270+622A>G		intron	N/A	ENSP00000361845.3
	ZMPSTE24	ENST00000472583.1	TSL:4	n.486+622A>G		intron	N/A
	ZMPSTE24	ENST00000479131.5	TSL:4	n.489+622A>G		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.252 AC: 38352 AN: 151976 Hom.: 4975 Cov.: 32

Gnomad AFR AF: 0.267

Gnomad AMI AF: 0.130

Gnomad AMR AF: 0.180

Gnomad ASJ AF: 0.222

Gnomad EAS AF: 0.240

Gnomad SAS AF: 0.179

Gnomad FIN AF: 0.295

Gnomad MID AF: 0.179

Gnomad NFE AF: 0.263

Gnomad OTH AF: 0.240

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

GnomAD4 genome AF: 0.252 AC: 38349 AN: 152094 Hom.: 4975 Cov.: 32 AF XY: 0.252 AC XY: 18700 AN XY: 74340

African (AFR) AF: 0.266 AC: 11048 AN: 41486

American (AMR) AF: 0.180 AC: 2754 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.222 AC: 768 AN: 3466

East Asian (EAS) AF: 0.240 AC: 1241 AN: 5174

South Asian (SAS) AF: 0.178 AC: 857 AN: 4828

European-Finnish (FIN) AF: 0.295 AC: 3111 AN: 10556

Middle Eastern (MID) AF: 0.169 AC: 49 AN: 290

European-Non Finnish (NFE) AF: 0.263 AC: 17898 AN: 67984

Other (OTH) AF: 0.239 AC: 505 AN: 2110

Alfa AF: 0.263 Hom.: 867

Bravo AF: 0.244

Asia WGS AF: 0.218 AC: 757 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	4.7
DANN	Benign	0.87
PhyloP100		-1.1
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: rs7514099; hg19: chr1-40727279; COSMIC: COSV65638924; COSMIC: COSV65638924;