Genetic Variant ZMPSTE24:n.-194A>G (chr1-40258078-A-G) – ACMG Classification: Benign (-9 pts)

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_StrongBS1_SupportingBS2

The ENST00000675937.1(ZMPSTE24):n.-194A>G variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00346 in 933,600 control chromosomes in the GnomAD database, including 32 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as not provided (no stars).

Frequency

Genomes: 𝑓 0.0042 ( 13 hom., cov: 32)

Exomes 𝑓: 0.0033 ( 19 hom. )

Consequence

ZMPSTE24
ENST00000675937.1 5_prime_UTR_premature_start_codon_gain

Scores

Clinical Significance

not provided no classification provided O:1

Conservation

PhyloP100: -0.717

Publications

1 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 links:

ZMPSTE24-DT (HGNC:55402): (ZMPSTE24 divergent transcript)

ZMPSTE24-DT links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -9 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.91).

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00418 (631/150840) while in subpopulation NFE AF = 0.00385 (260/67592). AF 95% confidence interval is 0.00346. There are 13 homozygotes in GnomAd4. There are 358 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

BS2

High Homozygotes in GnomAd4 at 13 AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZMPSTE24	NM_005857.5 link	c.-194A>G		upstream_gene_variant		ENST00000372759.4	NP_005848.2	O75844
ZMPSTE24	XM_047427590.1 link	c.-194A>G		upstream_gene_variant			XP_047283546.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ZMPSTE24	ENST00000372759.4 link	c.-194A>G		upstream_gene_variant		1	NM_005857.5	ENSP00000361845.3		O75844

Frequencies

GnomAD3 genomes

AF:

0.00419

AC:

631

AN:

150724

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000242

Gnomad AMI

AF:

0.0157

Gnomad AMR

AF:

0.000132

Gnomad ASJ

AF:

0.0266

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00319

Gnomad FIN

AF:

0.0236

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.00385

Gnomad OTH

AF:

0.00193

GnomAD4 exome

AF:

0.00332

AC:

2597

AN:

782760

Hom.:

Cov.:

AF XY:

0.00334

AC XY:

1330

AN XY:

398634

show subpopulations

African (AFR)

AF:

0.000102

AC:

AN:

19606

American (AMR)

AF:

0.0000402

AC:

AN:

24902

Ashkenazi Jewish (ASJ)

AF:

0.0249

AC:

399

AN:

16028

East Asian (EAS)

AF:

0.00

AC:

AN:

33892

South Asian (SAS)

AF:

0.00334

AC:

194

AN:

58150

European-Finnish (FIN)

AF:

0.0219

AC:

693

AN:

31594

Middle Eastern (MID)

AF:

0.00352

AC:

AN:

2554

European-Non Finnish (NFE)

AF:

0.00205

AC:

1147

AN:

559348

Other (OTH)

AF:

0.00414

AC:

152

AN:

36686

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

122

243

365

486

608

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.00418

AC:

631

AN:

150840

Hom.:

Cov.:

AF XY:

0.00485

AC XY:

358

AN XY:

73778

show subpopulations

African (AFR)

AF:

0.0000242

AC:

AN:

41378

American (AMR)

AF:

0.000132

AC:

AN:

15192

Ashkenazi Jewish (ASJ)

AF:

0.0266

AC:

AN:

3454

East Asian (EAS)

AF:

0.00

AC:

AN:

5042

South Asian (SAS)

AF:

0.00319

AC:

AN:

4702

European-Finnish (FIN)

AF:

0.0236

AC:

241

AN:

10194

Middle Eastern (MID)

AF:

0.00680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00385

AC:

260

AN:

67592

Other (OTH)

AF:

0.00191

AC:

AN:

2098

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

107

134

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00831

Hom.:

Bravo

AF:

0.00187

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

-0.91

CADD

Benign

1.5

(source)

DANN

Benign

0.34

PhyloP100

-0.72

PromoterAI

-0.063

Neutral

(source)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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1-40258078-A-G

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over