rs2076697

Variant names:

• chr1-40271917-T-C
• rs2076697
• NM_005857.5:c.651T>C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_005857.5(ZMPSTE24):​c.651T>C​(p.Asp217Asp) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0846 in 1,613,256 control chromosomes in the GnomAD database, including 7,390 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.080 (652 hom., cov: 32)
  • Exomes 𝑓: 0.085 (6738 hom.)
• Consequence: ZMPSTE24 NM_005857.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9 O:1
• Conservation: PhyloP100: 1.17
• Publications: 18 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.52).
• BP6: Variant 1-40271917-T-C is Benign according to our data. Variant chr1-40271917-T-C is described in ClinVar as Benign. ClinVar VariationId is 95316.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=1.17 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.218 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.651T>C	p.Asp217Asp	synonymous	Exon 6 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.651T>C	p.Asp217Asp	synonymous	Exon 6 of 10	ENSP00000361845.3	O75844
	ZMPSTE24	ENST00000869004.1		c.651T>C	p.Asp217Asp	synonymous	Exon 6 of 10	ENSP00000539063.1
	ZMPSTE24	ENST00000869005.1		c.651T>C	p.Asp217Asp	synonymous	Exon 6 of 9	ENSP00000539064.1

Frequencies

GnomAD3 genomes AF: 0.0804 AC: 12228 AN: 152172 Hom.: 648 Cov.: 32

Gnomad AFR AF: 0.0598

Gnomad AMI AF: 0.110

Gnomad AMR AF: 0.114

Gnomad ASJ AF: 0.0830

Gnomad EAS AF: 0.229

Gnomad SAS AF: 0.199

Gnomad FIN AF: 0.0619

Gnomad MID AF: 0.0791

Gnomad NFE AF: 0.0679

Gnomad OTH AF: 0.0837

GnomAD2 exomes AF: 0.108 AC: 27106 AN: 251210 AF XY: 0.110

Gnomad AFR exome AF: 0.0627

Gnomad AMR exome AF: 0.150

Gnomad ASJ exome AF: 0.0806

Gnomad EAS exome AF: 0.236

Gnomad FIN exome AF: 0.0658

Gnomad NFE exome AF: 0.0690

Gnomad OTH exome AF: 0.0920

GnomAD4 exome AF: 0.0850 AC: 124166 AN: 1460966 Hom.: 6738 Cov.: 32 AF XY: 0.0884 AC XY: 64244 AN XY: 726792

African (AFR) AF: 0.0592 AC: 1981 AN: 33464

American (AMR) AF: 0.146 AC: 6544 AN: 44700

Ashkenazi Jewish (ASJ) AF: 0.0818 AC: 2137 AN: 26114

East Asian (EAS) AF: 0.236 AC: 9338 AN: 39590

South Asian (SAS) AF: 0.192 AC: 16574 AN: 86184

European-Finnish (FIN) AF: 0.0637 AC: 3402 AN: 53378

Middle Eastern (MID) AF: 0.0751 AC: 433 AN: 5764

European-Non Finnish (NFE) AF: 0.0703 AC: 78139 AN: 1111424

Other (OTH) AF: 0.0931 AC: 5618 AN: 60348

GnomAD4 genome AF: 0.0804 AC: 12243 AN: 152290 Hom.: 652 Cov.: 32 AF XY: 0.0822 AC XY: 6122 AN XY: 74476

African (AFR) AF: 0.0598 AC: 2487 AN: 41574

American (AMR) AF: 0.114 AC: 1745 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.0830 AC: 288 AN: 3470

East Asian (EAS) AF: 0.229 AC: 1185 AN: 5176

South Asian (SAS) AF: 0.199 AC: 960 AN: 4830

European-Finnish (FIN) AF: 0.0619 AC: 658 AN: 10624

Middle Eastern (MID) AF: 0.0816 AC: 24 AN: 294

European-Non Finnish (NFE) AF: 0.0679 AC: 4620 AN: 68014

Other (OTH) AF: 0.0833 AC: 176 AN: 2112

Alfa AF: 0.0754 Hom.: 692

Bravo AF: 0.0833

Asia WGS AF: 0.217 AC: 752 AN: 3472

EpiCase AF: 0.0677

EpiControl AF: 0.0683

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	3	not provided (4)
-	-	1	Lethal tight skin contracture syndrome (1)
-	-	1	Mandibuloacral dysplasia with type B lipodystrophy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.52
CADD	Benign	11
DANN	Benign	0.56
PhyloP100		1.2
Mutation Taster		=92/8	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: rs2076697; hg19: chr1-40737589; COSMIC: COSV65638821; COSMIC: COSV65638821;