1-40281212-T-G

Variant names:

• chr1-40281212-T-G
• rs78985808
• NM_005857.5:c.770-131T>G

Variant summary

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

The NM_005857.5(ZMPSTE24):​c.770-131T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000129 in 776,334 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: 0.0000013 (0 hom.)
• Consequence: ZMPSTE24 NM_005857.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.655
• 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: 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=-0.83).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZMPSTE24	NM_005857.5	c.770-131T>G		intron_variant	Intron 6 of 9	ENST00000372759.4	NP_005848.2
ZMPSTE24	XM_047427590.1	c.*914T>G		3_prime_UTR_variant	Exon 7 of 7		XP_047283546.1
ZMPSTE24	XM_047427582.1	c.521-131T>G		intron_variant	Intron 5 of 8		XP_047283538.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ZMPSTE24	ENST00000372759.4	c.770-131T>G		intron_variant	Intron 6 of 9	1	NM_005857.5	ENSP00000361845.3
ZMPSTE24	ENST00000674703.1	n.*611-131T>G		intron_variant	Intron 7 of 10			ENSP00000501674.1
ZMPSTE24	ENST00000675754.1	n.*512-131T>G		intron_variant	Intron 7 of 10			ENSP00000502555.1
ZMPSTE24	ENST00000675937.1	n.*15-131T>G		intron_variant	Intron 7 of 10			ENSP00000502683.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000129 AC: 1 AN: 776334 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 406746

African (AFR) AF: 0.00 AC: 0 AN: 19092

American (AMR) AF: 0.00 AC: 0 AN: 33478

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 20042

East Asian (EAS) AF: 0.00 AC: 0 AN: 35102

South Asian (SAS) AF: 0.00 AC: 0 AN: 64460

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 39478

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3262

European-Non Finnish (NFE) AF: 0.00000191 AC: 1 AN: 523988

Other (OTH) AF: 0.00 AC: 0 AN: 37432

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	1.8
DANN	Benign	0.53
PhyloP100		-0.66

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: rs78985808; hg19: chr1-40746884;