1-40258087-C-T

Variant names:

• chr1-40258087-C-T
• rs1057515563
• ENST00000675937.1:n.-185C>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The ENST00000675937.1(ZMPSTE24):​n.-185C>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000455 in 880,072 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000045 (0 hom.)
• Consequence: ZMPSTE24 ENST00000675937.1 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.34
• Publications: 0 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-DT (HGNC:55402): (ZMPSTE24 divergent transcript)

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.77).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZMPSTE24	NM_005857.5	c.-185C>T		upstream_gene_variant		ENST00000372759.4	NP_005848.2
ZMPSTE24	XM_047427590.1	c.-185C>T		upstream_gene_variant			XP_047283546.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ZMPSTE24	ENST00000372759.4	c.-185C>T		upstream_gene_variant		1	NM_005857.5	ENSP00000361845.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000455 AC: 4 AN: 880072 Hom.: 0 Cov.: 12 AF XY: 0.00000673 AC XY: 3 AN XY: 445770

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 21672

American (AMR) AF: 0.00 AC: 0 AN: 27960

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 16982

East Asian (EAS) AF: 0.00 AC: 0 AN: 35440

South Asian (SAS) AF: 0.00 AC: 0 AN: 61636

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 32872

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2764

European-Non Finnish (NFE) AF: 0.00000624 AC: 4 AN: 640672

Other (OTH) AF: 0.00 AC: 0 AN: 40074

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.054799), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
CADD	Benign	4.5
DANN	Benign	0.77
PhyloP100		-1.3
PromoterAI		-0.092	Neutral

Splicing

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

Other links and lift over

dbSNP: rs1057515563; hg19: chr1-40723759;