rs187549487

Positions:

• chr1-40258078-A-G

Variant summary

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

The ENST00000675937.1(ZMPSTE24):​c.-194A>G variant causes a 5 prime UTR, NMD transcript change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00346 in 933,600 control chromosomes in the GnomAD database, including 32 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 0.0042 (13 hom., cov: 32)
  • Exomes 𝑓: 0.0033 (19 hom.)
• Consequence: ZMPSTE24 ENST00000675937.1 5_prime_UTR, NMD_transcript
• Clinical Significance: not provided no classification provided O:1
• Conservation: PhyloP100: -0.717

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=-0.91).
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00418 (631/150840) while in subpopulation NFE AF= 0.00385 (260/67592). AF 95% confidence interval is 0.00346. There are 13 homozygotes in gnomad4. There are 358 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAd4 at 13 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ZMPSTE24	ENST00000675937.1	c.-194A>G		5_prime_UTR_variant, NMD_transcript_variant	1/11			ENSP00000502683
ZMPSTE24	ENST00000674703.1			upstream_gene_variant				ENSP00000501674

Frequencies

GnomAD3 genomes AF: 0.00419 AC: 631 AN: 150724 Hom.: 13 Cov.: 32

Gnomad AFR AF: 0.0000242

Gnomad AMI AF: 0.0157

Gnomad AMR AF: 0.000132

Gnomad ASJ AF: 0.0266

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00319

Gnomad FIN AF: 0.0236

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00385

Gnomad OTH AF: 0.00193

GnomAD4 exome AF: 0.00332 AC: 2597 AN: 782760 Hom.: 19 Cov.: 11 AF XY: 0.00334 AC XY: 1330 AN XY: 398634

Gnomad4 AFR exome AF: 0.000102

Gnomad4 AMR exome AF: 0.0000402

Gnomad4 ASJ exome AF: 0.0249

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00334

Gnomad4 FIN exome AF: 0.0219

Gnomad4 NFE exome AF: 0.00205

Gnomad4 OTH exome AF: 0.00414

GnomAD4 genome AF: 0.00418 AC: 631 AN: 150840 Hom.: 13 Cov.: 32 AF XY: 0.00485 AC XY: 358 AN XY: 73778

Gnomad4 AFR AF: 0.0000242

Gnomad4 AMR AF: 0.000132

Gnomad4 ASJ AF: 0.0266

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00319

Gnomad4 FIN AF: 0.0236

Gnomad4 NFE AF: 0.00385

Gnomad4 OTH AF: 0.00191

Alfa AF: 0.00831 Hom.: 3

Bravo AF: 0.00187

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	-0.91
CADD	Benign	1.5
DANN	Benign	0.34

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs187549487; hg19: chr1-40723750;