1-40258100-A-C

Position:

• chr1-40258100-A-C

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BS1_Supporting BS2

The ENST00000675937.1(ZMPSTE24):​n.-172A>C 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 0.000992 in 1,134,620 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0010 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00099 (8 hom.)
• Consequence: ZMPSTE24 ENST00000675937.1 non_coding_transcript_exon
• Clinical Significance: Uncertain significance criteria provided, single submitter U:2
• Conservation: PhyloP100: 0.244

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]

ACMG classification

Verdict is Benign. Variant got -9 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.00102 (152/148902) while in subpopulation EAS AF= 0.0243 (118/4848). AF 95% confidence interval is 0.0208. There are 0 homozygotes in gnomad4. There are 81 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAdExome4 at 8 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ZMPSTE24	ENST00000674703.1	n.-172A>C		non_coding_transcript_exon_variant	1/11			ENSP00000501674.1
ZMPSTE24	ENST00000675937.1	n.-172A>C		non_coding_transcript_exon_variant	1/11			ENSP00000502683.1
ZMPSTE24	ENST00000674703.1	n.-172A>C		5_prime_UTR_variant	1/11			ENSP00000501674.1
ZMPSTE24	ENST00000675937.1	n.-172A>C		5_prime_UTR_variant	1/11			ENSP00000502683.1

Frequencies

GnomAD3 genomes AF: 0.00101 AC: 151 AN: 148776 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000466

Gnomad ASJ AF: 0.00555

Gnomad EAS AF: 0.0243

Gnomad SAS AF: 0.000441

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000448

Gnomad OTH AF: 0.000976

GnomAD4 exome AF: 0.000988 AC: 974 AN: 985718 Hom.: 8 Cov.: 13 AF XY: 0.00103 AC XY: 510 AN XY: 496998

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00344

Gnomad4 EAS exome AF: 0.0218

Gnomad4 SAS exome AF: 0.0000909

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000454

Gnomad4 OTH exome AF: 0.00167

GnomAD4 genome AF: 0.00102 AC: 152 AN: 148902 Hom.: 0 Cov.: 32 AF XY: 0.00111 AC XY: 81 AN XY: 72742

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.000465

Gnomad4 ASJ AF: 0.00555

Gnomad4 EAS AF: 0.0243

Gnomad4 SAS AF: 0.000440

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000448

Gnomad4 OTH AF: 0.00145

Bravo AF: 0.00102

Asia WGS AF: 0.00866 AC: 30 AN: 3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, single submitter

Submissions by phenotype

Lethal tight skin contracture syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Mandibuloacral dysplasia Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	9.4
DANN	Benign	0.72

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs151221982; hg19: chr1-40723772;