chr1-40286090-G-A

Position:

• chr1-40286090-G-A

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BS1_Supporting BS2

The NM_005857.5(ZMPSTE24):​c.1059+61G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00221 in 1,445,246 control chromosomes in the GnomAD database, including 13 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 0.0016 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0023 (13 hom.)
• Consequence: ZMPSTE24 NM_005857.5 intron
• Clinical Significance: not provided no classification provided O:1
• Conservation: PhyloP100: 0.207

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]

ACMG classification

Verdict is Benign. Variant got -9 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00158 (241/152188) while in subpopulation NFE AF= 0.00212 (144/68010). AF 95% confidence interval is 0.00184. There are 0 homozygotes in gnomad4. There are 116 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAdExome4 at 13 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ZMPSTE24	NM_005857.5	c.1059+61G>A		intron_variant		ENST00000372759.4	NP_005848.2
ZMPSTE24	XM_047427582.1	c.810+61G>A		intron_variant			XP_047283538.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ZMPSTE24	ENST00000372759.4	c.1059+61G>A		intron_variant		1	NM_005857.5	ENSP00000361845.3
ZMPSTE24	ENST00000674703.1	n.*900+61G>A		intron_variant				ENSP00000501674.1
ZMPSTE24	ENST00000675754.1	n.*801+61G>A		intron_variant				ENSP00000502555.1
ZMPSTE24	ENST00000675937.1	n.*304+61G>A		intron_variant				ENSP00000502683.1

Frequencies

GnomAD3 genomes AF: 0.00159 AC: 242 AN: 152070 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00157

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000830

Gnomad FIN AF: 0.00397

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.00212

Gnomad OTH AF: 0.00191

GnomAD4 exome AF: 0.00228 AC: 2953 AN: 1293058 Hom.: 13 AF XY: 0.00230 AC XY: 1496 AN XY: 649624

Gnomad4 AFR exome AF: 0.000169

Gnomad4 AMR exome AF: 0.000571

Gnomad4 ASJ exome AF: 0.000243

Gnomad4 EAS exome AF: 0.0000268

Gnomad4 SAS exome AF: 0.00123

Gnomad4 FIN exome AF: 0.00381

Gnomad4 NFE exome AF: 0.00262

Gnomad4 OTH exome AF: 0.00152

GnomAD4 genome AF: 0.00158 AC: 241 AN: 152188 Hom.: 0 Cov.: 31 AF XY: 0.00156 AC XY: 116 AN XY: 74400

Gnomad4 AFR AF: 0.000482

Gnomad4 AMR AF: 0.00157

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000831

Gnomad4 FIN AF: 0.00397

Gnomad4 NFE AF: 0.00212

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.00212 Hom.: 0

Bravo AF: 0.00156

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: not provided

Submissions summary: Other:1

Revision: no classification provided

Submissions by phenotype

not provided Other:1

not provided, no classification provided

literature only

ZMPSTE24 homepage - Leiden Muscular Dystrophy pages

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	1.3
DANN	Benign	0.72

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

LitVar

Other links and lift over

dbSNP: rs188058932; hg19: chr1-40751762;