1-40258290-C-G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_005857.5(ZMPSTE24):​c.19C>G​(p.Leu7Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,766 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. L7L) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

ZMPSTE24
NM_005857.5 missense

Scores

1
18

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.841

Publications

0 publications found
Variant links:
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

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.09806585).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
ZMPSTE24NM_005857.5 linkc.19C>G p.Leu7Val missense_variant Exon 1 of 10 ENST00000372759.4 NP_005848.2 O75844
ZMPSTE24XM_047427590.1 linkc.19C>G p.Leu7Val missense_variant Exon 1 of 7 XP_047283546.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
ZMPSTE24ENST00000372759.4 linkc.19C>G p.Leu7Val missense_variant Exon 1 of 10 1 NM_005857.5 ENSP00000361845.3 O75844

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD2 exomes
AF:
0.00000797
AC:
2
AN:
250994
AF XY:
0.00000737
show subpopulations
Gnomad AFR exome
AF:
0.0000615
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000137
AC:
2
AN:
1461766
Hom.:
0
Cov.:
31
AF XY:
0.00000138
AC XY:
1
AN XY:
727194
show subpopulations
African (AFR)
AF:
0.0000299
AC:
1
AN:
33480
American (AMR)
AF:
0.00
AC:
0
AN:
44724
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
26136
East Asian (EAS)
AF:
0.00
AC:
0
AN:
39700
South Asian (SAS)
AF:
0.0000116
AC:
1
AN:
86258
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
53302
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5766
European-Non Finnish (NFE)
AF:
0.00
AC:
0
AN:
1112004
Other (OTH)
AF:
0.00
AC:
0
AN:
60396
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.475
Heterozygous variant carriers
0
1
1
2
2
3
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Variant carriers
0
2
4
6
8
10
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
GnomAD4 genome
Cov.:
32
ExAC
AF:
0.0000165
AC:
2

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.064
BayesDel_addAF
Benign
-0.39
T
BayesDel_noAF
Benign
-0.62
CADD
Benign
17
DANN
Benign
0.97
DEOGEN2
Benign
0.26
T
Eigen
Benign
-0.28
Eigen_PC
Benign
-0.12
FATHMM_MKL
Benign
0.52
D
LIST_S2
Benign
0.63
T
M_CAP
Benign
0.0037
T
MetaRNN
Benign
0.098
T
MetaSVM
Benign
-0.90
T
MutationAssessor
Benign
0.81
L
PhyloP100
0.84
PrimateAI
Uncertain
0.53
T
PROVEAN
Benign
-0.60
N
REVEL
Benign
0.094
Sift
Benign
0.37
T
Sift4G
Benign
0.077
T
Polyphen
0.0
B
Vest4
0.15
MutPred
0.20
Gain of catalytic residue at L7 (P = 0.0223);
MVP
0.25
MPC
0.18
ClinPred
0.084
T
GERP RS
3.5
PromoterAI
-0.0091
Neutral
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.6
Varity_R
0.088
gMVP
0.51
Mutation Taster
=87/13
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

Publications

Other links and lift over

dbSNP: rs777639293; hg19: chr1-40723962; API