NM_005857.5:c.46G>A

Variant names:

• chr1-40258317-G-A
• rs1046247
• NM_005857.5:c.46G>A

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_005857.5(ZMPSTE24):​c.46G>A​(p.Glu16Lys) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E16Q) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ZMPSTE24 NM_005857.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.80
• Publications: 0 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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.46G>A	p.Glu16Lys	missense	Exon 1 of 10	NP_005848.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZMPSTE24	ENST00000372759.4	TSL:1 MANE Select	c.46G>A	p.Glu16Lys	missense	Exon 1 of 10	ENSP00000361845.3	O75844
	ZMPSTE24	ENST00000869004.1		c.46G>A	p.Glu16Lys	missense	Exon 1 of 10	ENSP00000539063.1
	ZMPSTE24	ENST00000869005.1		c.46G>A	p.Glu16Lys	missense	Exon 1 of 9	ENSP00000539064.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.37
BayesDel_addAF	Uncertain	0.16	D
BayesDel_noAF	Uncertain	-0.010
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.31	T
Eigen	Benign	0.12
Eigen_PC	Uncertain	0.27
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Uncertain	0.87	D
M_CAP	Uncertain	0.10	D
MetaRNN	Uncertain	0.48	T
MetaSVM	Benign	-0.51	T
MutationAssessor	Benign	1.7	L
PhyloP100		6.8
PrimateAI	Uncertain	0.76	T
PROVEAN	Benign	-1.3	N
REVEL	Uncertain	0.32
Sift	Uncertain	0.014	D
Sift4G	Benign	0.086	T
Polyphen		0.84	P
Vest4		0.56
MutPred		0.47		Gain of methylation at E16 (P = 0.0173)
MVP		0.41
MPC		0.59
ClinPred		0.98	D
GERP RS		5.3
PromoterAI		-0.10	Neutral
Varity_R		0.65
gMVP		0.76
Mutation Taster		=69/31	polymorphism

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: rs1046247; hg19: chr1-40723989; COSMIC: COSV108205606; COSMIC: COSV108205606;