chr1-40281212-T-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -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

Publications

0 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=-0.9).

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 VariationId is 140539.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 21 AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein
ZMPSTE24	NM_005857.5 link	c.770-131T>C	intron_variant	Intron 6 of 9	ENST00000372759.4	NP_005848.2
ZMPSTE24	XM_047427590.1 link	c.*914T>C	3_prime_UTR_variant	Exon 7 of 7		XP_047283546.1
ZMPSTE24	XM_047427582.1 link	c.521-131T>C	intron_variant	Intron 5 of 8		XP_047283538.1

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein
ZMPSTE24	ENST00000372759.4 link	c.770-131T>C	intron_variant	Intron 6 of 9	1	NM_005857.5	ENSP00000361845.3
ZMPSTE24	ENST00000674703.1 link	n.*611-131T>C	intron_variant	Intron 7 of 10			ENSP00000501674.1
ZMPSTE24	ENST00000675754.1 link	n.*512-131T>C	intron_variant	Intron 7 of 10			ENSP00000502555.1
ZMPSTE24	ENST00000675937.1 link	n.*15-131T>C	intron_variant	Intron 7 of 10			ENSP00000502683.1

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

African (AFR)

AF:

0.0327

AC:

625

AN:

19086

American (AMR)

AF:

0.00242

AC:

AN:

33476

Ashkenazi Jewish (ASJ)

AF:

0.0000499

AC:

AN:

20042

East Asian (EAS)

AF:

0.00

AC:

AN:

35102

South Asian (SAS)

AF:

0.0000776

AC:

AN:

64460

European-Finnish (FIN)

AF:

0.00

AC:

AN:

39478

Middle Eastern (MID)

AF:

0.00521

AC:

AN:

3262

European-Non Finnish (NFE)

AF:

0.000401

AC:

210

AN:

523984

Other (OTH)

AF:

0.00264

AC:

AN:

37432

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.511

Heterozygous variant carriers

127

170

212

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00939

AC:

1430

AN:

152354

Hom.:

Cov.:

AF XY:

0.00907

AC XY:

676

AN XY:

74508

show subpopulations

African (AFR)

AF:

0.0319

AC:

1326

AN:

41576

American (AMR)

AF:

0.00444

AC:

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5190

South Asian (SAS)

AF:

0.00

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000235

AC:

AN:

68036

Other (OTH)

AF:

0.00946

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.495

Heterozygous variant carriers

131

196

262

327

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

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

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Nov 04, 2019

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

-0.90

CADD

Benign

2.2

(source)

DANN

Benign

0.53

PhyloP100

-0.66

Mutation Taster

=100/0

polymorphism

(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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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