chr1-40271844-T-G

Variant names:

• chr1-40271844-T-G
• rs6677717
• NM_005857.5:c.628-50T>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.628-50T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.987 in 1,598,900 control chromosomes in the GnomAD database, including 779,277 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.99 (74279 hom., cov: 32)
  • Exomes 𝑓: 0.99 (704998 hom.)
• Consequence: ZMPSTE24 NM_005857.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3 O:1
• Conservation: PhyloP100: -0.228
• 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=-0.93).
• BP6: Variant 1-40271844-T-G is Benign according to our data. Variant chr1-40271844-T-G is described in ClinVar as Benign. ClinVar VariationId is 140535.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.99 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.628-50T>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.628-50T>G		intron	N/A	ENSP00000361845.3
	ZMPSTE24	ENST00000674703.1		n.*469-50T>G		intron	N/A	ENSP00000501674.1
	ZMPSTE24	ENST00000675754.1		n.*370-50T>G		intron	N/A	ENSP00000502555.1

Frequencies

GnomAD3 genomes AF: 0.987 AC: 150287 AN: 152192 Hom.: 74221 Cov.: 32

Gnomad AFR AF: 0.998

Gnomad AMI AF: 0.982

Gnomad AMR AF: 0.996

Gnomad ASJ AF: 0.924

Gnomad EAS AF: 1.00

Gnomad SAS AF: 0.990

Gnomad FIN AF: 0.958

Gnomad MID AF: 0.994

Gnomad NFE AF: 0.986

Gnomad OTH AF: 0.988

GnomAD2 exomes AF: 0.985 AC: 242837 AN: 246500 AF XY: 0.985

Gnomad AFR exome AF: 0.998

Gnomad AMR exome AF: 0.997

Gnomad ASJ exome AF: 0.930

Gnomad EAS exome AF: 1.00

Gnomad FIN exome AF: 0.959

Gnomad NFE exome AF: 0.987

Gnomad OTH exome AF: 0.984

GnomAD4 exome AF: 0.987 AC: 1428075 AN: 1446590 Hom.: 704998 Cov.: 25 AF XY: 0.987 AC XY: 710899 AN XY: 720344

African (AFR) AF: 0.998 AC: 33059 AN: 33124

American (AMR) AF: 0.997 AC: 44067 AN: 44210

Ashkenazi Jewish (ASJ) AF: 0.929 AC: 24083 AN: 25910

East Asian (EAS) AF: 1.00 AC: 39465 AN: 39466

South Asian (SAS) AF: 0.985 AC: 83812 AN: 85052

European-Finnish (FIN) AF: 0.961 AC: 50676 AN: 52748

Middle Eastern (MID) AF: 0.972 AC: 5549 AN: 5706

European-Non Finnish (NFE) AF: 0.989 AC: 1088443 AN: 1100568

Other (OTH) AF: 0.985 AC: 58921 AN: 59806

GnomAD4 genome AF: 0.987 AC: 150404 AN: 152310 Hom.: 74279 Cov.: 32 AF XY: 0.986 AC XY: 73483 AN XY: 74492

African (AFR) AF: 0.998 AC: 41487 AN: 41558

American (AMR) AF: 0.996 AC: 15234 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.924 AC: 3205 AN: 3470

East Asian (EAS) AF: 1.00 AC: 5188 AN: 5188

South Asian (SAS) AF: 0.990 AC: 4780 AN: 4830

European-Finnish (FIN) AF: 0.958 AC: 10169 AN: 10612

Middle Eastern (MID) AF: 0.993 AC: 292 AN: 294

European-Non Finnish (NFE) AF: 0.986 AC: 67063 AN: 68032

Other (OTH) AF: 0.988 AC: 2090 AN: 2116

Alfa AF: 0.980 Hom.: 18556

Bravo AF: 0.991

Asia WGS AF: 0.994 AC: 3450 AN: 3472

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	1.3
DANN	Benign	0.76
PhyloP100		-0.23
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: rs6677717; hg19: chr1-40737516;