Genetic Variant ZMPSTE24:n.-172A>C (chr1-40258100-A-C) – 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.-172A>C variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000992 in 1,134,620 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0010 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00099 ( 8 hom. )

Consequence

ZMPSTE24
ENST00000675937.1 non_coding_transcript_exon

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:2

Conservation

PhyloP100: 0.244

Publications

2 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=-0.83).

BS1

Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.00102 (152/148902) while in subpopulation EAS AF = 0.0243 (118/4848). AF 95% confidence interval is 0.0208. There are 0 homozygotes in GnomAd4. There are 81 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 GnomAdExome4 at 8 AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZMPSTE24	NM_005857.5 link	c.-172A>C		upstream_gene_variant		ENST00000372759.4	NP_005848.2	O75844
ZMPSTE24	XM_047427590.1 link	c.-172A>C		upstream_gene_variant			XP_047283546.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ZMPSTE24	ENST00000372759.4 link	c.-172A>C		upstream_gene_variant		1	NM_005857.5	ENSP00000361845.3		O75844

Frequencies

GnomAD3 genomes

AF:

0.00101

AC:

151

AN:

148776

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000466

Gnomad ASJ

AF:

0.00555

Gnomad EAS

AF:

0.0243

Gnomad SAS

AF:

0.000441

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000448

Gnomad OTH

AF:

0.000976

GnomAD4 exome

AF:

0.000988

AC:

974

AN:

985718

Hom.:

Cov.:

AF XY:

0.00103

AC XY:

510

AN XY:

496998

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

24022

American (AMR)

AF:

0.00

AC:

AN:

33222

Ashkenazi Jewish (ASJ)

AF:

0.00344

AC:

AN:

18300

East Asian (EAS)

AF:

0.0218

AC:

799

AN:

36674

South Asian (SAS)

AF:

0.0000909

AC:

AN:

65990

European-Finnish (FIN)

AF:

0.00

AC:

AN:

34230

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3002

European-Non Finnish (NFE)

AF:

0.0000454

AC:

AN:

726454

Other (OTH)

AF:

0.00167

AC:

AN:

43824

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.510

Heterozygous variant carriers

136

181

226

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.00102

AC:

152

AN:

148902

Hom.:

Cov.:

AF XY:

0.00111

AC XY:

AN XY:

72742

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

40986

American (AMR)

AF:

0.000465

AC:

AN:

15048

Ashkenazi Jewish (ASJ)

AF:

0.00555

AC:

AN:

3426

East Asian (EAS)

AF:

0.0243

AC:

118

AN:

4848

South Asian (SAS)

AF:

0.000440

AC:

AN:

4542

European-Finnish (FIN)

AF:

0.00

AC:

AN:

9788

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.0000448

AC:

AN:

67012

Other (OTH)

AF:

0.00145

AC:

AN:

2072

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00102

Asia WGS

AF:

0.00866

AC:

AN:

3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Lethal tight skin contracture syndrome

Uncertain:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mandibuloacral dysplasia

Uncertain:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.83

CADD

Benign

9.4

(source)

DANN

Benign

0.72

PhyloP100

0.24

PromoterAI

-0.0020

Neutral

(source)

Splicing

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

Publications

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1-40258100-A-C

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