Genetic Variant ZMPSTE24:c.628-50T>C (chr1-40271844-T-C) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_005857.5(ZMPSTE24):c.628-50T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000691 in 1,446,652 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as not provided (no stars).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

ZMPSTE24
NM_005857.5 intron

Scores

Clinical Significance

not provided no classification provided O:1

Conservation

PhyloP100: -0.228

Publications

9 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

ZMPSTE24 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.83).

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
ZMPSTE24	NM_005857.5 link	c.628-50T>C	intron_variant	Intron 5 of 9	ENST00000372759.4	NP_005848.2	O75844
ZMPSTE24	XM_047427582.1 link	c.379-50T>C	intron_variant	Intron 4 of 8		XP_047283538.1
ZMPSTE24	XM_047427590.1 link	c.628-50T>C	intron_variant	Intron 5 of 6		XP_047283546.1

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein	UniProt
ZMPSTE24	ENST00000372759.4 link	c.628-50T>C	intron_variant	Intron 5 of 9	1	NM_005857.5	ENSP00000361845.3	O75844
ZMPSTE24	ENST00000674703.1 link	n.*469-50T>C	intron_variant	Intron 6 of 10			ENSP00000501674.1	A0A6Q8PF67
ZMPSTE24	ENST00000675754.1 link	n.*370-50T>C	intron_variant	Intron 6 of 10			ENSP00000502555.1	A0A6Q8PH40
ZMPSTE24	ENST00000675937.1 link	n.628-50T>C	intron_variant	Intron 5 of 10			ENSP00000502683.1	A0A6Q8PHG9

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.91e-7

AC:

AN:

1446652

Hom.:

Cov.:

AF XY:

0.00000139

AC XY:

AN XY:

720366

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

33124

American (AMR)

AF:

0.0000226

AC:

AN:

44212

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25910

East Asian (EAS)

AF:

0.00

AC:

AN:

39466

South Asian (SAS)

AF:

0.00

AC:

AN:

85054

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52758

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5708

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1100614

Other (OTH)

AF:

0.00

AC:

AN:

59806

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.375

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Significance: not provided

Submissions summary: Other:1

Revision: no classification provided

LINK: link

Submissions by phenotype

not provided

Other:1

ZMPSTE24 homepage - Leiden Muscular Dystrophy pages

Significance:not provided

Review Status:no classification provided

Collection Method:literature only

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.83

CADD

Benign

1.3

(source)

DANN

Benign

0.86

PhyloP100

-0.23

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over