1-40276227-C-T

Variant names:

• chr1-40276227-C-T
• rs6676644
• NM_005857.5:c.769+4192C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_005857.5(ZMPSTE24):​c.769+4192C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.905 in 152,274 control chromosomes in the GnomAD database, including 62,467 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as not provided (no stars).

• Frequency: Genomes: 𝑓 0.90 (62467 hom., cov: 32)
• Consequence: ZMPSTE24 NM_005857.5 intron
• Clinical Significance: not provided no classification provided O:1
• Conservation: PhyloP100: 0.290
• Publications: 3 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.98).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.963 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZMPSTE24	NM_005857.5	c.769+4192C>T		intron_variant	Intron 6 of 9	ENST00000372759.4	NP_005848.2
ZMPSTE24	XM_047427582.1	c.520+4192C>T		intron_variant	Intron 5 of 8		XP_047283538.1
ZMPSTE24	XM_047427590.1	c.770-3893C>T		intron_variant	Intron 6 of 6		XP_047283546.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ZMPSTE24	ENST00000372759.4	c.769+4192C>T		intron_variant	Intron 6 of 9	1	NM_005857.5	ENSP00000361845.3
ZMPSTE24	ENST00000674703.1	n.*610+4192C>T		intron_variant	Intron 7 of 10			ENSP00000501674.1
ZMPSTE24	ENST00000675754.1	n.*511+4192C>T		intron_variant	Intron 7 of 10			ENSP00000502555.1
ZMPSTE24	ENST00000675937.1	n.770-3893C>T		intron_variant	Intron 6 of 10			ENSP00000502683.1

Frequencies

GnomAD3 genomes AF: 0.904 AC: 137625 AN: 152156 Hom.: 62401 Cov.: 32

Gnomad AFR AF: 0.971

Gnomad AMI AF: 0.942

Gnomad AMR AF: 0.903

Gnomad ASJ AF: 0.784

Gnomad EAS AF: 0.864

Gnomad SAS AF: 0.926

Gnomad FIN AF: 0.860

Gnomad MID AF: 0.864

Gnomad NFE AF: 0.880

Gnomad OTH AF: 0.884

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.905 AC: 137750 AN: 152274 Hom.: 62467 Cov.: 32 AF XY: 0.905 AC XY: 67361 AN XY: 74456

African (AFR) AF: 0.971 AC: 40357 AN: 41564

American (AMR) AF: 0.903 AC: 13813 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.784 AC: 2719 AN: 3468

East Asian (EAS) AF: 0.864 AC: 4482 AN: 5188

South Asian (SAS) AF: 0.926 AC: 4475 AN: 4832

European-Finnish (FIN) AF: 0.860 AC: 9108 AN: 10596

Middle Eastern (MID) AF: 0.871 AC: 256 AN: 294

European-Non Finnish (NFE) AF: 0.879 AC: 59813 AN: 68010

Other (OTH) AF: 0.885 AC: 1870 AN: 2112

Alfa AF: 0.883 Hom.: 114784

Bravo AF: 0.910

Asia WGS AF: 0.887 AC: 3085 AN: 3478

ClinVar

Significance: not provided

Submissions summary: Other:1

Revision: no classification provided

Submissions by phenotype

not provided Other:1

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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	-0.98
CADD	Benign	3.3
DANN	Benign	0.67
PhyloP100		0.29
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: rs6676644; hg19: chr1-40741899;