1-40258375-C-A

Variant names:

• chr1-40258375-C-A
• rs2124573747
• NM_005857.5:c.104C>A

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_005857.5(ZMPSTE24):​c.104C>A​(p.Thr35Asn) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: ZMPSTE24 NM_005857.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.16
• 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: 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: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.2935913).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZMPSTE24	NM_005857.5	c.104C>A	p.Thr35Asn	missense_variant	Exon 1 of 10	ENST00000372759.4	NP_005848.2
ZMPSTE24	XM_047427590.1	c.104C>A	p.Thr35Asn	missense_variant	Exon 1 of 7		XP_047283546.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ZMPSTE24	ENST00000372759.4	c.104C>A	p.Thr35Asn	missense_variant	Exon 1 of 10	1	NM_005857.5	ENSP00000361845.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Mar 18, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces threonine with asparagine at codon 35 of the ZMPSTE24 protein (p.Thr35Asn). There is a small physicochemical difference between threonine and asparagine. This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with ZMPSTE24-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.52
CADD	Benign	22
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.46	T
Eigen	Benign	-0.11
Eigen_PC	Benign	0.092
FATHMM_MKL	Benign	0.62	D
LIST_S2	Uncertain	0.88	D
M_CAP	Benign	0.022	T
MetaRNN	Benign	0.29	T
MetaSVM	Benign	-0.49	T
MutationAssessor	Benign	0.74	N
PhyloP100		4.2
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	-1.9	N
REVEL	Benign	0.17
Sift	Benign	0.30	T
Sift4G	Benign	0.30	T
Polyphen		0.019	B
Vest4		0.59
MutPred		0.40		Gain of MoRF binding (P = 0.1103);
MVP		0.15
MPC		0.21
ClinPred		0.77	D
GERP RS		5.2
PromoterAI		-0.049	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.87
gMVP		0.71
Mutation Taster		=56/44	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: rs2124573747; hg19: chr1-40724047;