rs187549487

Variant names:

• chr1-40258078-A-G
• rs187549487
• ENST00000675937.1:n.-194A>G

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BS1_Supporting BS2

The ENST00000675937.1(ZMPSTE24):​n.-194A>G 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 0.00346 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_premature_start_codon_gain
• Clinical Significance: not provided no classification provided O:1
• Conservation: PhyloP100: -0.717
• Publications: 1 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: Benign. The variant received -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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAd4 at 13 AR,AD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000675937.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZMPSTE24	NM_005857.5	MANE Select	c.-194A>G		upstream_gene	N/A	NP_005848.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZMPSTE24	ENST00000675937.1		n.-194A>G		5_prime_UTR_premature_start_codon_gain	Exon 1 of 11	ENSP00000502683.1
	ZMPSTE24	ENST00000675937.1		n.-194A>G		non_coding_transcript_exon	Exon 1 of 11	ENSP00000502683.1
	ZMPSTE24	ENST00000675937.1		n.-194A>G		5_prime_UTR	Exon 1 of 11	ENSP00000502683.1

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

African (AFR) AF: 0.000102 AC: 2 AN: 19606

American (AMR) AF: 0.0000402 AC: 1 AN: 24902

Ashkenazi Jewish (ASJ) AF: 0.0249 AC: 399 AN: 16028

East Asian (EAS) AF: 0.00 AC: 0 AN: 33892

South Asian (SAS) AF: 0.00334 AC: 194 AN: 58150

European-Finnish (FIN) AF: 0.0219 AC: 693 AN: 31594

Middle Eastern (MID) AF: 0.00352 AC: 9 AN: 2554

European-Non Finnish (NFE) AF: 0.00205 AC: 1147 AN: 559348

Other (OTH) AF: 0.00414 AC: 152 AN: 36686

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

African (AFR) AF: 0.0000242 AC: 1 AN: 41378

American (AMR) AF: 0.000132 AC: 2 AN: 15192

Ashkenazi Jewish (ASJ) AF: 0.0266 AC: 92 AN: 3454

East Asian (EAS) AF: 0.00 AC: 0 AN: 5042

South Asian (SAS) AF: 0.00319 AC: 15 AN: 4702

European-Finnish (FIN) AF: 0.0236 AC: 241 AN: 10194

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.00385 AC: 260 AN: 67592

Other (OTH) AF: 0.00191 AC: 4 AN: 2098

Alfa AF: 0.00831 Hom.: 3

Bravo AF: 0.00187

ClinVar

ClinVar submissions as Germline

Significance: not provided

Revision: no classification provided

Pathogenic	VUS	Benign	Condition
-	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	1.5
DANN	Benign	0.34
PhyloP100		-0.72
PromoterAI		-0.063	Neutral

Splicing

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

Other links and lift over

dbSNP: rs187549487; hg19: chr1-40723750;