rs75470795

Variant names:

• chr1-40268618-A-C
• rs75470795
• NM_005857.5:c.474+83A>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

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
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2 O:1
• Conservation: PhyloP100: 0.0940
• Publications: 2 publications found

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

ACMG classification

Our verdict: Benign. The variant received -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 VariationId is 140527.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 50 AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZMPSTE24	NM_005857.5	c.474+83A>C		intron_variant	Intron 4 of 9	ENST00000372759.4	NP_005848.2
ZMPSTE24	XM_047427582.1	c.225+83A>C		intron_variant	Intron 3 of 8		XP_047283538.1
ZMPSTE24	XM_047427590.1	c.474+83A>C		intron_variant	Intron 4 of 6		XP_047283546.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ZMPSTE24	ENST00000372759.4	c.474+83A>C		intron_variant	Intron 4 of 9	1	NM_005857.5	ENSP00000361845.3
ZMPSTE24	ENST00000674703.1	n.*315+83A>C		intron_variant	Intron 5 of 10			ENSP00000501674.1
ZMPSTE24	ENST00000675754.1	n.*216+83A>C		intron_variant	Intron 5 of 10			ENSP00000502555.1
ZMPSTE24	ENST00000675937.1	n.474+83A>C		intron_variant	Intron 4 of 10			ENSP00000502683.1

Frequencies

GnomAD3 genomes AF: 0.0218 AC: 3319 AN: 152212 Hom.: 50 Cov.: 32

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

African (AFR) AF: 0.00445 AC: 79 AN: 17756

American (AMR) AF: 0.00876 AC: 242 AN: 27640

Ashkenazi Jewish (ASJ) AF: 0.0112 AC: 210 AN: 18732

East Asian (EAS) AF: 0.0000288 AC: 1 AN: 34718

South Asian (SAS) AF: 0.0131 AC: 817 AN: 62352

European-Finnish (FIN) AF: 0.0499 AC: 1851 AN: 37102

Middle Eastern (MID) AF: 0.0108 AC: 41 AN: 3790

European-Non Finnish (NFE) AF: 0.0327 AC: 16783 AN: 512842

Other (OTH) AF: 0.0225 AC: 816 AN: 36204

GnomAD4 genome AF: 0.0218 AC: 3320 AN: 152330 Hom.: 50 Cov.: 32 AF XY: 0.0216 AC XY: 1606 AN XY: 74494

African (AFR) AF: 0.00589 AC: 245 AN: 41578

American (AMR) AF: 0.00765 AC: 117 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00980 AC: 34 AN: 3468

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5188

South Asian (SAS) AF: 0.00912 AC: 44 AN: 4826

European-Finnish (FIN) AF: 0.0530 AC: 563 AN: 10618

Middle Eastern (MID) AF: 0.0136 AC: 4 AN: 294

European-Non Finnish (NFE) AF: 0.0328 AC: 2230 AN: 68042

Other (OTH) AF: 0.0180 AC: 38 AN: 2112

Alfa AF: 0.0314 Hom.: 105

Bravo AF: 0.0179

Asia WGS AF: 0.00866 AC: 30 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:2 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2 Other:1

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Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

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ZMPSTE24 homepage - Leiden Muscular Dystrophy pages

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Jan 06, 2020

GeneDx

Significance: Likely 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	-0.78
CADD	Benign	8.8
DANN	Benign	0.85
PhyloP100		0.094
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs75470795; hg19: chr1-40734290; COSMIC: COSV65639256; COSMIC: COSV65639256;