rs6664294

Positions:

• chr1-40292321-T-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_005857.5(ZMPSTE24):​c.1204-124T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.248 in 873,268 control chromosomes in the GnomAD database, including 27,590 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.25 (4829 hom., cov: 32)
  • Exomes 𝑓: 0.25 (22761 hom.)
• Consequence: ZMPSTE24 NM_005857.5 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.0570

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.71).
• BP6: Variant 1-40292321-T-C is Benign according to our data. Variant chr1-40292321-T-C is described in ClinVar as [Benign]. Clinvar id is 1260900.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.261 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ZMPSTE24	NM_005857.5	c.1204-124T>C		intron_variant		ENST00000372759.4
ZMPSTE24	XM_047427582.1	c.955-124T>C		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ZMPSTE24	ENST00000372759.4	c.1204-124T>C		intron_variant		1	NM_005857.5	P1

Frequencies

GnomAD3 genomes AF: 0.249 AC: 37783 AN: 151964 Hom.: 4828 Cov.: 32

Gnomad AFR AF: 0.257

Gnomad AMI AF: 0.129

Gnomad AMR AF: 0.171

Gnomad ASJ AF: 0.216

Gnomad EAS AF: 0.229

Gnomad SAS AF: 0.177

Gnomad FIN AF: 0.295

Gnomad MID AF: 0.193

Gnomad NFE AF: 0.264

Gnomad OTH AF: 0.239

GnomAD4 exome AF: 0.249 AC: 179224 AN: 721184 Hom.: 22761 AF XY: 0.244 AC XY: 93756 AN XY: 383682

Gnomad4 AFR exome AF: 0.255

Gnomad4 AMR exome AF: 0.164

Gnomad4 ASJ exome AF: 0.221

Gnomad4 EAS exome AF: 0.237

Gnomad4 SAS exome AF: 0.177

Gnomad4 FIN exome AF: 0.299

Gnomad4 NFE exome AF: 0.262

Gnomad4 OTH exome AF: 0.240

GnomAD4 genome AF: 0.248 AC: 37779 AN: 152084 Hom.: 4829 Cov.: 32 AF XY: 0.248 AC XY: 18400 AN XY: 74334

Gnomad4 AFR AF: 0.257

Gnomad4 AMR AF: 0.171

Gnomad4 ASJ AF: 0.216

Gnomad4 EAS AF: 0.229

Gnomad4 SAS AF: 0.176

Gnomad4 FIN AF: 0.295

Gnomad4 NFE AF: 0.264

Gnomad4 OTH AF: 0.239

Alfa AF: 0.253 Hom.: 2357

Bravo AF: 0.239

Asia WGS AF: 0.208 AC: 722 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Nov 13, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.71
CADD	Benign	14
DANN	Benign	0.89

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: rs6664294; hg19: chr1-40757993; COSMIC: COSV65639278;