Variant chr1-40268618-A-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_005857.5(ZMPSTE24):c.474+83A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0267 in 903,466 control chromosomes in the GnomAD database, including 416 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.022 ( 50 hom., cov: 32)

Exomes 𝑓: 0.028 ( 366 hom. )

Consequence

ZMPSTE24
NM_005857.5 intron

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:2O:1

Conservation

PhyloP100: 0.0940

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:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.78).

BP6

Variant 1-40268618-A-C is Benign according to our data. Variant chr1-40268618-A-C is described in ClinVar as [Likely_benign]. Clinvar id is 140527.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-40268618-A-C is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0218 (3320/152330) while in subpopulation NFE AF= 0.0328 (2230/68042). AF 95% confidence interval is 0.0316. There are 50 homozygotes in gnomad4. There are 1606 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 50 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	MANE	Protein
ZMPSTE24	NM_005857.5 linkuse as main transcript	c.474+83A>C	intron_variant	ENST00000372759.4	NP_005848.2
ZMPSTE24	XM_047427582.1 linkuse as main transcript	c.225+83A>C	intron_variant		XP_047283538.1
ZMPSTE24	XM_047427590.1 linkuse as main transcript	c.474+83A>C	intron_variant		XP_047283546.1

Ensembl

Gene	Transcript	HGVSc	Effect	TSL	MANE	Protein	Appris
ZMPSTE24	ENST00000372759.4 linkuse as main transcript	c.474+83A>C	intron_variant	1	NM_005857.5	ENSP00000361845	P1
ZMPSTE24	ENST00000674703.1 linkuse as main transcript	c.*315+83A>C	intron_variant, NMD_transcript_variant			ENSP00000501674
ZMPSTE24	ENST00000675754.1 linkuse as main transcript	c.*216+83A>C	intron_variant, NMD_transcript_variant			ENSP00000502555
ZMPSTE24	ENST00000675937.1 linkuse as main transcript	c.474+83A>C	intron_variant, NMD_transcript_variant			ENSP00000502683

Frequencies

GnomAD3 genomes

AF:

0.0218

AC:

3319

AN:

152212

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00591

Gnomad AMI

AF:

0.0482

Gnomad AMR

AF:

0.00766

Gnomad ASJ

AF:

0.00980

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.00911

Gnomad FIN

AF:

0.0530

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.0328

Gnomad OTH

AF:

0.0182

GnomAD4 exome

AF:

0.0277

AC:

20840

AN:

751136

Hom.:

366

AF XY:

0.0275

AC XY:

10915

AN XY:

396494

show subpopulations

Gnomad4 AFR exome

AF:

0.00445

Gnomad4 AMR exome

AF:

0.00876

Gnomad4 ASJ exome

AF:

0.0112

Gnomad4 EAS exome

AF:

0.0000288

Gnomad4 SAS exome

AF:

0.0131

Gnomad4 FIN exome

AF:

0.0499

Gnomad4 NFE exome

AF:

0.0327

Gnomad4 OTH exome

AF:

0.0225

GnomAD4 genome

AF:

0.0218

AC:

3320

AN:

152330

Hom.:

Cov.:

AF XY:

0.0216

AC XY:

1606

AN XY:

74494

show subpopulations

Gnomad4 AFR

AF:

0.00589

Gnomad4 AMR

AF:

0.00765

Gnomad4 ASJ

AF:

0.00980

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00912

Gnomad4 FIN

AF:

0.0530

Gnomad4 NFE

AF:

0.0328

Gnomad4 OTH

AF:

0.0180

Alfa

AF:

0.0282

Hom.:

Bravo

AF:

0.0179

Asia WGS

AF:

0.00866

AC:

AN:

3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:2Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2Other:1

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 06, 2020	- -
not provided, no classification provided	literature only	ZMPSTE24 homepage - Leiden Muscular Dystrophy pages	-	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.78

CADD

Benign

8.8

DANN

Benign

0.85

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over