rs6664294

Variant names:

• chr1-40292321-T-C
• rs6664294
• NM_005857.5:c.1204-124T>C

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_005857.5(ZMPSTE24):​c.1204-124T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.248 in 873,268 control chromosomes in the GnomAD database, including 27,590 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.25 (4829 hom., cov: 32)
  • Exomes 𝑓: 0.25 (22761 hom.)
• Consequence: ZMPSTE24 NM_005857.5 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.0570
• Publications: 3 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.71).
• BP6: Variant 1-40292321-T-C is Benign according to our data. Variant chr1-40292321-T-C is described in ClinVar as Benign. ClinVar VariationId is 1260900.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.261 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZMPSTE24	NM_005857.5	c.1204-124T>C		intron_variant	Intron 9 of 9	ENST00000372759.4	NP_005848.2
ZMPSTE24	XM_047427582.1	c.955-124T>C		intron_variant	Intron 8 of 8		XP_047283538.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ZMPSTE24	ENST00000372759.4	c.1204-124T>C		intron_variant	Intron 9 of 9	1	NM_005857.5	ENSP00000361845.3

Frequencies

GnomAD3 genomes AF: 0.249 AC: 37783 AN: 151964 Hom.: 4828 Cov.: 32

Gnomad AFR AF: 0.257

Gnomad AMI AF: 0.129

Gnomad AMR AF: 0.171

Gnomad ASJ AF: 0.216

Gnomad EAS AF: 0.229

Gnomad SAS AF: 0.177

Gnomad FIN AF: 0.295

Gnomad MID AF: 0.193

Gnomad NFE AF: 0.264

Gnomad OTH AF: 0.239

GnomAD4 exome AF: 0.249 AC: 179224 AN: 721184 Hom.: 22761 AF XY: 0.244 AC XY: 93756 AN XY: 383682

African (AFR) AF: 0.255 AC: 4609 AN: 18042

American (AMR) AF: 0.164 AC: 5454 AN: 33298

Ashkenazi Jewish (ASJ) AF: 0.221 AC: 4368 AN: 19738

East Asian (EAS) AF: 0.237 AC: 8531 AN: 36032

South Asian (SAS) AF: 0.177 AC: 11454 AN: 64664

European-Finnish (FIN) AF: 0.299 AC: 14326 AN: 47906

Middle Eastern (MID) AF: 0.179 AC: 460 AN: 2566

European-Non Finnish (NFE) AF: 0.262 AC: 121467 AN: 463282

Other (OTH) AF: 0.240 AC: 8555 AN: 35656

GnomAD4 genome AF: 0.248 AC: 37779 AN: 152084 Hom.: 4829 Cov.: 32 AF XY: 0.248 AC XY: 18400 AN XY: 74334

African (AFR) AF: 0.257 AC: 10646 AN: 41462

American (AMR) AF: 0.171 AC: 2611 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.216 AC: 750 AN: 3472

East Asian (EAS) AF: 0.229 AC: 1185 AN: 5178

South Asian (SAS) AF: 0.176 AC: 850 AN: 4830

European-Finnish (FIN) AF: 0.295 AC: 3115 AN: 10568

Middle Eastern (MID) AF: 0.184 AC: 54 AN: 294

European-Non Finnish (NFE) AF: 0.264 AC: 17947 AN: 67986

Other (OTH) AF: 0.239 AC: 504 AN: 2110

Alfa AF: 0.253 Hom.: 2612

Bravo AF: 0.239

Asia WGS AF: 0.208 AC: 722 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Nov 13, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.71
CADD	Benign	14
DANN	Benign	0.89
PhyloP100		-0.057
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: rs6664294; hg19: chr1-40757993; COSMIC: COSV65639278;