1-40257919-G-C

Variant names:

• chr1-40257919-G-C
• ENST00000567508.3:n.76C>G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The ENST00000567508.3(ZMPSTE24-DT):​n.76C>G variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000772 in 129,588 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000077 (0 hom.)
• Consequence: ZMPSTE24-DT ENST00000567508.3 non_coding_transcript_exon
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.72
• Publications: 0 publications found

Genes affected

ZMPSTE24-DT (HGNC:55402): (ZMPSTE24 divergent transcript)

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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ZMPSTE24-DT	ENST00000567508.3	n.76C>G		non_coding_transcript_exon_variant	Exon 1 of 1	6
ZMPSTE24	ENST00000674703.1	n.-353G>C		upstream_gene_variant				ENSP00000501674.1
ZMPSTE24	ENST00000675937.1	n.-353G>C		upstream_gene_variant				ENSP00000502683.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000772 AC: 1 AN: 129588 Hom.: 0 Cov.: 0 AF XY: 0.0000145 AC XY: 1 AN XY: 69152

African (AFR) AF: 0.00 AC: 0 AN: 4544

American (AMR) AF: 0.00 AC: 0 AN: 5990

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3638

East Asian (EAS) AF: 0.00 AC: 0 AN: 6492

South Asian (SAS) AF: 0.0000498 AC: 1 AN: 20064

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6262

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 526

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 74866

Other (OTH) AF: 0.00 AC: 0 AN: 7206

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	11
DANN	Benign	0.64
PhyloP100		1.7
PromoterAI		0.076	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

hg19: chr1-40723591;