chr1-40272009-C-T

Position:

• chr1-40272009-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1 PP3_Strong PP5_Moderate

The NM_005857.5(ZMPSTE24):​c.743C>T​(p.Pro248Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000161 in 1,611,784 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000016 (0 hom.)
• Consequence: ZMPSTE24 NM_005857.5 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:2 O:1
• Conservation: PhyloP100: 7.39

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 8 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
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.978
• PP5: Variant 1-40272009-C-T is Pathogenic according to our data. Variant chr1-40272009-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 4275.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr1-40272009-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ZMPSTE24	NM_005857.5	c.743C>T	p.Pro248Leu	missense_variant	6/10	ENST00000372759.4	NP_005848.2
ZMPSTE24	XM_047427582.1	c.494C>T	p.Pro165Leu	missense_variant	5/9		XP_047283538.1
ZMPSTE24	XM_047427590.1	c.743C>T	p.Pro248Leu	missense_variant	6/7		XP_047283546.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ZMPSTE24	ENST00000372759.4	c.743C>T	p.Pro248Leu	missense_variant	6/10	1	NM_005857.5	ENSP00000361845.3

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152124 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000164 AC: 24 AN: 1459660 Hom.: 0 Cov.: 32 AF XY: 0.00000275 AC XY: 2 AN XY: 726080

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000216

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152124 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74318

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000322 Hom.: 0

Bravo AF: 0.0000189

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2 Other:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1 Other:1

not provided, no classification provided	literature only	ZMPSTE24 homepage - Leiden Muscular Dystrophy pages	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	May 18, 2021	For these reasons, this variant has been classified as Pathogenic. 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: "Probably Damaging"; Align-GVGD: "Not Available"). This variant has been observed in individual(s) with mandibuloacral dysplasia (PMID: 18435794, 20814950). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 4275). This variant is not present in population databases (ExAC no frequency). This sequence change replaces proline with leucine at codon 248 of the ZMPSTE24 protein (p.Pro248Leu). There is a moderate physicochemical difference between proline and leucine. -

Mandibuloacral dysplasia with type B lipodystrophy Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Nov 01, 2010

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.41	D
BayesDel_noAF	Pathogenic	0.36
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.90	D
Eigen	Pathogenic	0.95
Eigen_PC	Pathogenic	0.88
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.97	D
M_CAP	Uncertain	0.10	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Uncertain	0.72	D
MutationAssessor	Pathogenic	3.9	H
PrimateAI	Uncertain	0.78	T
PROVEAN	Pathogenic	-8.9	D
REVEL	Pathogenic	0.84
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0030	D
Polyphen		1.0	D
Vest4		0.95
MutPred		0.87		Loss of methylation at K251 (P = 0.0718);
MVP		0.99
MPC		0.72
ClinPred		1.0	D
GERP RS		5.3
Varity_R		0.99
gMVP		0.79

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: rs121908095; hg19: chr1-40737681;