rs267607181

Positions:

• chr1-40271981-G-A
• chr1-40271981-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1 PP3_Moderate

The NM_005857.5(ZMPSTE24):​c.715G>A​(p.Glu239Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000513 in 1,461,106 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 Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000051 (0 hom.)
• Consequence: ZMPSTE24 NM_005857.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 9.37

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 Uncertain_significance. Variant got 4 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, 0.893

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ZMPSTE24	NM_005857.5	c.715G>A	p.Glu239Lys	missense_variant	6/10	ENST00000372759.4	NP_005848.2
ZMPSTE24	XM_047427582.1	c.466G>A	p.Glu156Lys	missense_variant	5/9		XP_047283538.1
ZMPSTE24	XM_047427590.1	c.715G>A	p.Glu239Lys	missense_variant	6/7		XP_047283546.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ZMPSTE24	ENST00000372759.4	c.715G>A	p.Glu239Lys	missense_variant	6/10	1	NM_005857.5	ENSP00000361845.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000119 AC: 3 AN: 251240 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135802

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000290

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000513 AC: 75 AN: 1461106 Hom.: 0 Cov.: 32 AF XY: 0.0000482 AC XY: 35 AN XY: 726856

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: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000648

Gnomad4 OTH exome AF: 0.0000331

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000766 Hom.: 0

Bravo AF: 0.0000302

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Mandibuloacral dysplasia with type B lipodystrophy Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Lethal tight skin contracture syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Aug 09, 2021

This sequence change replaces glutamic acid with lysine at codon 239 of the ZMPSTE24 protein (p.Glu239Lys). There is a small physicochemical difference between glutamic acid and lysine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals affected with ZMPSTE24-related conditions. ClinVar contains an entry for this variant (Variation ID: 874177). 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	0.29
BayesDel_addAF	Pathogenic	0.37	D
BayesDel_noAF	Pathogenic	0.30
CADD	Pathogenic	31
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.83	D
Eigen	Pathogenic	0.83
Eigen_PC	Pathogenic	0.81
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.97	D
M_CAP	Benign	0.038	D
MetaRNN	Pathogenic	0.89	D
MetaSVM	Uncertain	0.13	D
MutationAssessor	Uncertain	2.3	M
PrimateAI	Uncertain	0.74	T
PROVEAN	Uncertain	-3.5	D
REVEL	Pathogenic	0.69
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.025	D
Polyphen		0.98	D
Vest4		0.87
MVP		0.95
MPC		0.33
ClinPred		0.96	D
GERP RS		5.3
Varity_R		0.80
gMVP		0.89

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: rs267607181; hg19: chr1-40737653; COSMIC: COSV65639581; COSMIC: COSV65639581;