1-40267986-A-G

Variant names:

• chr1-40267986-A-G
• rs7516571
• NM_005857.5:c.357+114A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_005857.5(ZMPSTE24):​c.357+114A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.246 in 888,632 control chromosomes in the GnomAD database, including 27,870 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.25 (4981 hom., cov: 32)
  • Exomes 𝑓: 0.25 (22889 hom.)
• Consequence: ZMPSTE24 NM_005857.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2 O:1
• Conservation: PhyloP100: -1.13
• Publications: 10 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=-0.85).
• BP6: Variant 1-40267986-A-G is Benign according to our data. Variant chr1-40267986-A-G is described in ClinVar as Benign. ClinVar VariationId is 140525.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.262 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZMPSTE24	NM_005857.5	c.357+114A>G		intron_variant	Intron 3 of 9	ENST00000372759.4	NP_005848.2
ZMPSTE24	XM_047427582.1	c.108+114A>G		intron_variant	Intron 2 of 8		XP_047283538.1
ZMPSTE24	XM_047427590.1	c.357+114A>G		intron_variant	Intron 3 of 6		XP_047283546.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ZMPSTE24	ENST00000372759.4	c.357+114A>G		intron_variant	Intron 3 of 9	1	NM_005857.5	ENSP00000361845.3

Frequencies

GnomAD3 genomes AF: 0.252 AC: 38365 AN: 152038 Hom.: 4981 Cov.: 32

Gnomad AFR AF: 0.267

Gnomad AMI AF: 0.130

Gnomad AMR AF: 0.180

Gnomad ASJ AF: 0.222

Gnomad EAS AF: 0.240

Gnomad SAS AF: 0.179

Gnomad FIN AF: 0.294

Gnomad MID AF: 0.184

Gnomad NFE AF: 0.263

Gnomad OTH AF: 0.240

GnomAD4 exome AF: 0.245 AC: 180441 AN: 736474 Hom.: 22889 AF XY: 0.241 AC XY: 94798 AN XY: 393116

African (AFR) AF: 0.263 AC: 5146 AN: 19600

American (AMR) AF: 0.181 AC: 7557 AN: 41714

Ashkenazi Jewish (ASJ) AF: 0.223 AC: 4750 AN: 21292

East Asian (EAS) AF: 0.248 AC: 8921 AN: 35928

South Asian (SAS) AF: 0.178 AC: 12604 AN: 70948

European-Finnish (FIN) AF: 0.298 AC: 14461 AN: 48596

Middle Eastern (MID) AF: 0.187 AC: 815 AN: 4348

European-Non Finnish (NFE) AF: 0.257 AC: 117490 AN: 457792

Other (OTH) AF: 0.240 AC: 8697 AN: 36256

GnomAD4 genome AF: 0.252 AC: 38363 AN: 152158 Hom.: 4981 Cov.: 32 AF XY: 0.251 AC XY: 18700 AN XY: 74368

African (AFR) AF: 0.266 AC: 11052 AN: 41512

American (AMR) AF: 0.180 AC: 2747 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.222 AC: 770 AN: 3472

East Asian (EAS) AF: 0.240 AC: 1242 AN: 5184

South Asian (SAS) AF: 0.178 AC: 859 AN: 4826

European-Finnish (FIN) AF: 0.294 AC: 3113 AN: 10588

Middle Eastern (MID) AF: 0.173 AC: 51 AN: 294

European-Non Finnish (NFE) AF: 0.263 AC: 17905 AN: 67980

Other (OTH) AF: 0.239 AC: 506 AN: 2114

Alfa AF: 0.207 Hom.: 817

Bravo AF: 0.244

Asia WGS AF: 0.217 AC: 754 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2 Other: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

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	0.95
DANN	Benign	0.73
PhyloP100		-1.1
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs7516571; hg19: chr1-40733658; COSMIC: COSV65638895; COSMIC: COSV65638895;