Variant 1-40281212-T-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.770-131T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00266 in 928,676 control chromosomes in the GnomAD database, including 33 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0094 ( 21 hom., cov: 32)

Exomes 𝑓: 0.0013 ( 12 hom. )

Consequence

ZMPSTE24
NM_005857.5 intron

Scores

Clinical Significance

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

Conservation

PhyloP100: -0.655

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=-0.9).

BP6

Variant 1-40281212-T-C is Benign according to our data. Variant chr1-40281212-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 140539.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-40281212-T-C is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00939 (1430/152354) while in subpopulation AFR AF= 0.0319 (1326/41576). AF 95% confidence interval is 0.0305. There are 21 homozygotes in gnomad4. There are 676 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 21 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	#exon/exons	MANE	Protein	UniProt
ZMPSTE24	NM_005857.5 linkuse as main transcript	c.770-131T>C	intron_variant		ENST00000372759.4	NP_005848.2	O75844
ZMPSTE24	XM_047427590.1 linkuse as main transcript	c.*914T>C	3_prime_UTR_variant	7/7		XP_047283546.1
ZMPSTE24	XM_047427582.1 linkuse as main transcript	c.521-131T>C	intron_variant			XP_047283538.1

Ensembl

Gene	Transcript	HGVSc	Effect	TSL	MANE	Protein	UniProt
ZMPSTE24	ENST00000372759.4 linkuse as main transcript	c.770-131T>C	intron_variant	1	NM_005857.5	ENSP00000361845.3	O75844
ZMPSTE24	ENST00000674703.1 linkuse as main transcript	n.*611-131T>C	intron_variant			ENSP00000501674.1	A0A6Q8PF67
ZMPSTE24	ENST00000675754.1 linkuse as main transcript	n.*512-131T>C	intron_variant			ENSP00000502555.1	A0A6Q8PH40
ZMPSTE24	ENST00000675937.1 linkuse as main transcript	n.*15-131T>C	intron_variant			ENSP00000502683.1	A0A6Q8PHG9

Frequencies

GnomAD3 genomes

AF:

0.00936

AC:

1425

AN:

152236

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0319

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00445

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000235

Gnomad OTH

AF:

0.00956

GnomAD4 exome

AF:

0.00134

AC:

1038

AN:

776322

Hom.:

AF XY:

0.00118

AC XY:

480

AN XY:

406736

show subpopulations

Gnomad4 AFR exome

AF:

0.0327

Gnomad4 AMR exome

AF:

0.00242

Gnomad4 ASJ exome

AF:

0.0000499

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000776

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000401

Gnomad4 OTH exome

AF:

0.00264

GnomAD4 genome

AF:

0.00939

AC:

1430

AN:

152354

Hom.:

Cov.:

AF XY:

0.00907

AC XY:

676

AN XY:

74508

show subpopulations

Gnomad4 AFR

AF:

0.0319

Gnomad4 AMR

AF:

0.00444

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000235

Gnomad4 OTH

AF:

0.00946

Alfa

AF:

0.00888

Hom.:

Bravo

AF:

0.0103

Asia WGS

AF:

0.00202

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

not provided, no classification provided	literature only	ZMPSTE24 homepage - Leiden Muscular Dystrophy pages	-	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 04, 2019	- -
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

-0.90

CADD

Benign

2.2

DANN

Benign

0.53

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

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