chr1-40285988-T-C

Position:

• chr1-40285988-T-C

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1 PM2 PP3_Strong PP5

The NM_005857.5(ZMPSTE24):​c.1018T>C​(p.Trp340Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 31)
• Consequence: ZMPSTE24 NM_005857.5 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1 O:1
• Conservation: PhyloP100: 7.67

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 9 ACMG points.

• PM1: In a topological_domain Nuclear (size 130) in uniprot entity FACE1_HUMAN there are 9 pathogenic changes around while only 0 benign (100%) in NM_005857.5
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.992
• PP5: Variant 1-40285988-T-C is Pathogenic according to our data. Variant chr1-40285988-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 4272.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr1-40285988-T-C is described in Lovd as [Pathogenic]. Variant chr1-40285988-T-C is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ZMPSTE24	NM_005857.5	c.1018T>C	p.Trp340Arg	missense_variant	8/10	ENST00000372759.4	NP_005848.2
ZMPSTE24	XM_047427582.1	c.769T>C	p.Trp257Arg	missense_variant	7/9		XP_047283538.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ZMPSTE24	ENST00000372759.4	c.1018T>C	p.Trp340Arg	missense_variant	8/10	1	NM_005857.5	ENSP00000361845.3

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1 Other:1

Revision: no assertion criteria provided

Submissions by phenotype

Mandibuloacral dysplasia with type B lipodystrophy Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Aug 15, 2003

- -

not provided Other:1

not provided, no classification provided

literature only

ZMPSTE24 homepage - Leiden Muscular Dystrophy pages

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.41	D
BayesDel_noAF	Pathogenic	0.35
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.93	D
Eigen	Pathogenic	0.85
Eigen_PC	Pathogenic	0.76
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.88	D
M_CAP	Uncertain	0.28	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Uncertain	0.62	D
MutationAssessor	Pathogenic	3.9	H
PrimateAI	Pathogenic	0.92	D
PROVEAN	Pathogenic	-13	D
REVEL	Pathogenic	0.87
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0020	D
Polyphen		0.99	D
Vest4		0.96
MutPred		0.95		Gain of disorder (P = 0.0035);
MVP		1.0
MPC		0.94
ClinPred		1.0	D
GERP RS		4.9
Varity_R		0.98
gMVP		0.94

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

Publications

LitVar

Other links and lift over

dbSNP: rs121908093; hg19: chr1-40751660;