rs10489432

Variant names:

• chr1-40293559-A-G
• rs10489432
• NM_005857.5:c.*890A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_005857.5(ZMPSTE24):​c.*890A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0799 in 152,290 control chromosomes in the GnomAD database, including 632 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.080 (632 hom., cov: 32)
  • Failed GnomAD Quality Control
• Consequence: ZMPSTE24 NM_005857.5 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3 O:1
• Conservation: PhyloP100: -1.11
• Publications: 11 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 Gene-Disease associations (from GenCC):

• lethal restrictive dermopathy

  Inheritance: AR, AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, Ambry Genetics, Orphanet
• mandibuloacral dysplasia with type B lipodystrophy

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, Ambry Genetics, ClinGen, Genomics England PanelApp
• restrictive dermopathy 1

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
• Hutchinson-Gilford progeria syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 1-40293559-A-G is Benign according to our data. Variant chr1-40293559-A-G is described in ClinVar as Benign. ClinVar VariationId is 140501.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.216 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005857.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZMPSTE24	NM_005857.5	MANE Select	c.*890A>G		3_prime_UTR	Exon 10 of 10	NP_005848.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZMPSTE24	ENST00000372759.4	TSL:1 MANE Select	c.*890A>G		3_prime_UTR	Exon 10 of 10	ENSP00000361845.3	O75844
	ZMPSTE24	ENST00000869004.1		c.*890A>G		3_prime_UTR	Exon 10 of 10	ENSP00000539063.1
	ZMPSTE24	ENST00000869005.1		c.*890A>G		3_prime_UTR	Exon 9 of 9	ENSP00000539064.1

Frequencies

GnomAD3 genomes AF: 0.0798 AC: 12146 AN: 152172 Hom.: 627 Cov.: 32

Gnomad AFR AF: 0.0624

Gnomad AMI AF: 0.110

Gnomad AMR AF: 0.113

Gnomad ASJ AF: 0.0833

Gnomad EAS AF: 0.226

Gnomad SAS AF: 0.197

Gnomad FIN AF: 0.0524

Gnomad MID AF: 0.0759

Gnomad NFE AF: 0.0673

Gnomad OTH AF: 0.0804

GnomAD4 exome Data not reliable, filtered out with message: AC0 AC: 0 AN: 0 Hom.: 0 Cov.: 0 AC XY: 0 AN XY: 0

African (AFR) AC: 0 AN: 0

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AC: 0 AN: 0

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AC: 0 AN: 0

Other (OTH) AC: 0 AN: 0

GnomAD4 genome AF: 0.0799 AC: 12163 AN: 152290 Hom.: 632 Cov.: 32 AF XY: 0.0819 AC XY: 6097 AN XY: 74458

African (AFR) AF: 0.0624 AC: 2592 AN: 41570

American (AMR) AF: 0.113 AC: 1732 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.0833 AC: 289 AN: 3468

East Asian (EAS) AF: 0.227 AC: 1176 AN: 5182

South Asian (SAS) AF: 0.197 AC: 950 AN: 4826

European-Finnish (FIN) AF: 0.0524 AC: 556 AN: 10610

Middle Eastern (MID) AF: 0.0782 AC: 23 AN: 294

European-Non Finnish (NFE) AF: 0.0673 AC: 4577 AN: 68026

Other (OTH) AF: 0.0795 AC: 168 AN: 2112

Alfa AF: 0.0752 Hom.: 1973

Bravo AF: 0.0844

Asia WGS AF: 0.213 AC: 741 AN: 3476

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Lethal tight skin contracture syndrome (1)
-	-	1	Mandibuloacral dysplasia with type B lipodystrophy (1)
-	-	1	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	0.037
DANN	Benign	0.41
PhyloP100		-1.1
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs10489432; hg19: chr1-40759231;