rs188058932

Variant names:

• chr1-40286090-G-A
• rs188058932
• NM_005857.5:c.1059+61G>A

Your query was ambiguous. Multiple possible variants found:

• chr1-40286090-G-A
• chr1-40286090-G-T

Variant summary

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

The NM_005857.5(ZMPSTE24):​c.1059+61G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00221 in 1,445,246 control chromosomes in the GnomAD database, including 13 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 0.0016 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0023 (13 hom.)
• Consequence: ZMPSTE24 NM_005857.5 intron
• Clinical Significance: not provided no classification provided O:1
• Conservation: PhyloP100: 0.207
• 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 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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00158 (241/152188) while in subpopulation NFE AF = 0.00212 (144/68010). AF 95% confidence interval is 0.00184. There are 0 homozygotes in GnomAd4. There are 116 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAdExome4 at 13 AR,AD gene

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.1059+61G>A		intron	N/A	NP_005848.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZMPSTE24	ENST00000372759.4	TSL:1 MANE Select	c.1059+61G>A		intron	N/A	ENSP00000361845.3	O75844
	ZMPSTE24	ENST00000869004.1		c.1059+61G>A		intron	N/A	ENSP00000539063.1
	ZMPSTE24	ENST00000869005.1		c.954+4563G>A		intron	N/A	ENSP00000539064.1

Frequencies

GnomAD3 genomes AF: 0.00159 AC: 242 AN: 152070 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00157

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000830

Gnomad FIN AF: 0.00397

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.00212

Gnomad OTH AF: 0.00191

GnomAD4 exome AF: 0.00228 AC: 2953 AN: 1293058 Hom.: 13 AF XY: 0.00230 AC XY: 1496 AN XY: 649624

African (AFR) AF: 0.000169 AC: 5 AN: 29544

American (AMR) AF: 0.000571 AC: 24 AN: 42028

Ashkenazi Jewish (ASJ) AF: 0.000243 AC: 6 AN: 24712

East Asian (EAS) AF: 0.0000268 AC: 1 AN: 37326

South Asian (SAS) AF: 0.00123 AC: 99 AN: 80430

European-Finnish (FIN) AF: 0.00381 AC: 196 AN: 51486

Middle Eastern (MID) AF: 0.000917 AC: 5 AN: 5452

European-Non Finnish (NFE) AF: 0.00262 AC: 2534 AN: 967634

Other (OTH) AF: 0.00152 AC: 83 AN: 54446

GnomAD4 genome AF: 0.00158 AC: 241 AN: 152188 Hom.: 0 Cov.: 31 AF XY: 0.00156 AC XY: 116 AN XY: 74400

African (AFR) AF: 0.000482 AC: 20 AN: 41534

American (AMR) AF: 0.00157 AC: 24 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.000831 AC: 4 AN: 4816

European-Finnish (FIN) AF: 0.00397 AC: 42 AN: 10590

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

European-Non Finnish (NFE) AF: 0.00212 AC: 144 AN: 68010

Other (OTH) AF: 0.00189 AC: 4 AN: 2114

Alfa AF: 0.00212 Hom.: 0

Bravo AF: 0.00156

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions

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	-0.81
CADD	Benign	1.3
DANN	Benign	0.72
PhyloP100		0.21
Mutation Taster		=100/0	polymorphism

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: rs188058932; hg19: chr1-40751762;