rs16827109

Variant names:

• chr1-40270145-T-G
• rs16827109
• NM_005857.5:c.627+18T>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.627+18T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0982 in 1,613,024 control chromosomes in the GnomAD database, including 8,239 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.090 (716 hom., cov: 32)
  • Exomes 𝑓: 0.099 (7523 hom.)
• Consequence: ZMPSTE24 NM_005857.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4 O:1
• Conservation: PhyloP100: 0.241
• Publications: 9 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: Genomics England PanelApp, Ambry Genetics, ClinGen, Labcorp Genetics (formerly Invitae), Orphanet
• 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=-0.75).
• BP6: Variant 1-40270145-T-G is Benign according to our data. Variant chr1-40270145-T-G is described in ClinVar as Benign. ClinVar VariationId is 140531.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.145 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZMPSTE24	NM_005857.5	MANE Select	c.627+18T>G		intron	N/A	NP_005848.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZMPSTE24	ENST00000372759.4	TSL:1 MANE Select	c.627+18T>G		intron	N/A	ENSP00000361845.3
	ZMPSTE24	ENST00000674703.1		n.*468+18T>G		intron	N/A	ENSP00000501674.1
	ZMPSTE24	ENST00000675754.1		n.*369+18T>G		intron	N/A	ENSP00000502555.1

Frequencies

GnomAD3 genomes AF: 0.0901 AC: 13718 AN: 152170 Hom.: 714 Cov.: 32

Gnomad AFR AF: 0.0647

Gnomad AMI AF: 0.0428

Gnomad AMR AF: 0.135

Gnomad ASJ AF: 0.0565

Gnomad EAS AF: 0.153

Gnomad SAS AF: 0.153

Gnomad FIN AF: 0.0925

Gnomad MID AF: 0.0918

Gnomad NFE AF: 0.0884

Gnomad OTH AF: 0.0833

GnomAD2 exomes AF: 0.107 AC: 26839 AN: 251184 AF XY: 0.108

Gnomad AFR exome AF: 0.0627

Gnomad AMR exome AF: 0.145

Gnomad ASJ exome AF: 0.0635

Gnomad EAS exome AF: 0.162

Gnomad FIN exome AF: 0.0894

Gnomad NFE exome AF: 0.0892

Gnomad OTH exome AF: 0.101

GnomAD4 exome AF: 0.0990 AC: 144638 AN: 1460736 Hom.: 7523 Cov.: 32 AF XY: 0.0995 AC XY: 72322 AN XY: 726764

African (AFR) AF: 0.0616 AC: 2059 AN: 33450

American (AMR) AF: 0.140 AC: 6238 AN: 44678

Ashkenazi Jewish (ASJ) AF: 0.0598 AC: 1561 AN: 26110

East Asian (EAS) AF: 0.132 AC: 5220 AN: 39592

South Asian (SAS) AF: 0.147 AC: 12658 AN: 86214

European-Finnish (FIN) AF: 0.0899 AC: 4790 AN: 53302

Middle Eastern (MID) AF: 0.0685 AC: 394 AN: 5748

European-Non Finnish (NFE) AF: 0.0952 AC: 105750 AN: 1111292

Other (OTH) AF: 0.0989 AC: 5968 AN: 60350

GnomAD4 genome AF: 0.0902 AC: 13738 AN: 152288 Hom.: 716 Cov.: 32 AF XY: 0.0923 AC XY: 6874 AN XY: 74466

African (AFR) AF: 0.0645 AC: 2683 AN: 41572

American (AMR) AF: 0.136 AC: 2081 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.0565 AC: 196 AN: 3470

East Asian (EAS) AF: 0.153 AC: 791 AN: 5182

South Asian (SAS) AF: 0.154 AC: 743 AN: 4830

European-Finnish (FIN) AF: 0.0925 AC: 981 AN: 10604

Middle Eastern (MID) AF: 0.0918 AC: 27 AN: 294

European-Non Finnish (NFE) AF: 0.0884 AC: 6014 AN: 68018

Other (OTH) AF: 0.0866 AC: 183 AN: 2112

Alfa AF: 0.0897 Hom.: 951

Bravo AF: 0.0918

Asia WGS AF: 0.131 AC: 456 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (4)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.75
CADD	Benign	9.0
DANN	Benign	0.78
PhyloP100		0.24
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.2
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: rs16827109; hg19: chr1-40735817; COSMIC: COSV65638901; COSMIC: COSV65638901;