1-40271844-T-G

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_005857.5(ZMPSTE24):c.628-50T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.987 in 1,598,900 control chromosomes in the GnomAD database, including 779,277 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.99 ( 74279 hom., cov: 32)

Exomes 𝑓: 0.99 ( 704998 hom. )

Consequence

ZMPSTE24
NM_005857.5 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3O: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: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.93).

BP6

Variant 1-40271844-T-G is Benign according to our data. Variant chr1-40271844-T-G is described in ClinVar as [Benign]. Clinvar id is 140535.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.99 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
ZMPSTE24	NM_005857.5 link	c.628-50T>G	intron_variant	Intron 5 of 9	ENST00000372759.4	NP_005848.2	O75844
ZMPSTE24	XM_047427582.1 link	c.379-50T>G	intron_variant	Intron 4 of 8		XP_047283538.1
ZMPSTE24	XM_047427590.1 link	c.628-50T>G	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>G	intron_variant	Intron 5 of 9	1	NM_005857.5	ENSP00000361845.3	O75844
ZMPSTE24	ENST00000674703.1 link	n.*469-50T>G	intron_variant	Intron 6 of 10			ENSP00000501674.1	A0A6Q8PF67
ZMPSTE24	ENST00000675754.1 link	n.*370-50T>G	intron_variant	Intron 6 of 10			ENSP00000502555.1	A0A6Q8PH40
ZMPSTE24	ENST00000675937.1 link	n.628-50T>G	intron_variant	Intron 5 of 10			ENSP00000502683.1	A0A6Q8PHG9

Frequencies

GnomAD3 genomes

AF:

0.987

AC:

150287

AN:

152192

Hom.:

74221

Cov.:

show subpopulations

Gnomad AFR

AF:

0.998

Gnomad AMI

AF:

0.982

Gnomad AMR

AF:

0.996

Gnomad ASJ

AF:

0.924

Gnomad EAS

AF:

1.00

Gnomad SAS

AF:

0.990

Gnomad FIN

AF:

0.958

Gnomad MID

AF:

0.994

Gnomad NFE

AF:

0.986

Gnomad OTH

AF:

0.988

GnomAD2 exomes

AF:

0.985

AC:

242837

AN:

246500

AF XY:

0.985

show subpopulations

Gnomad AFR exome

AF:

0.998

Gnomad AMR exome

AF:

0.997

Gnomad ASJ exome

AF:

0.930

Gnomad EAS exome

AF:

1.00

Gnomad FIN exome

AF:

0.959

Gnomad NFE exome

AF:

0.987

Gnomad OTH exome

AF:

0.984

GnomAD4 exome

AF:

0.987

AC:

1428075

AN:

1446590

Hom.:

704998

Cov.:

AF XY:

0.987

AC XY:

710899

AN XY:

720344

show subpopulations

African (AFR)

AF:

0.998

AC:

33059

AN:

33124

American (AMR)

AF:

0.997

AC:

44067

AN:

44210

Ashkenazi Jewish (ASJ)

AF:

0.929

AC:

24083

AN:

25910

East Asian (EAS)

AF:

1.00

AC:

39465

AN:

39466

South Asian (SAS)

AF:

0.985

AC:

83812

AN:

85052

European-Finnish (FIN)

AF:

0.961

AC:

50676

AN:

52748

Middle Eastern (MID)

AF:

0.972

AC:

5549

AN:

5706

European-Non Finnish (NFE)

AF:

0.989

AC:

1088443

AN:

1100568

Other (OTH)

AF:

0.985

AC:

58921

AN:

59806

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.508

Heterozygous variant carriers

894

1788

2681

3575

4469

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.987

AC:

150404

AN:

152310

Hom.:

74279

Cov.:

AF XY:

0.986

AC XY:

73483

AN XY:

74492

show subpopulations

African (AFR)

AF:

0.998

AC:

41487

AN:

41558

American (AMR)

AF:

0.996

AC:

15234

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.924

AC:

3205

AN:

3470

East Asian (EAS)

AF:

1.00

AC:

5188

AN:

5188

South Asian (SAS)

AF:

0.990

AC:

4780

AN:

4830

European-Finnish (FIN)

AF:

0.958

AC:

10169

AN:

10612

Middle Eastern (MID)

AF:

0.993

AC:

292

AN:

294

European-Non Finnish (NFE)

AF:

0.986

AC:

67063

AN:

68032

Other (OTH)

AF:

0.988

AC:

2090

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

197

295

394

492

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.980

Hom.:

18556

Bravo

AF:

0.991

Asia WGS

AF:

0.994

AC:

3450

AN:

3472

ClinVar

Significance: Benign

Submissions summary: Benign:3Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2Other:1

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

ZMPSTE24 homepage - Leiden Muscular Dystrophy pages

Significance:not provided

Review Status:no classification provided

Collection Method:literature only

- -

Nov 13, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:1

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.93

CADD

Benign

1.3

(source)

DANN

Benign

0.76

PhyloP100

-0.23

Mutation Taster

=100/0

polymorphism (auto)

(source)

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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1-40271844-T-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