chr3-155144383-C-T
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_007289.4(MME):c.1342C>T(p.Arg448*) variant causes a stop gained change. The variant allele was found at a frequency of 0.0000713 in 1,612,384 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_007289.4 stop_gained
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000658 AC: 10AN: 151954Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000798 AC: 20AN: 250696Hom.: 0 AF XY: 0.0000812 AC XY: 11AN XY: 135490
GnomAD4 exome AF: 0.0000719 AC: 105AN: 1460430Hom.: 0 Cov.: 30 AF XY: 0.0000757 AC XY: 55AN XY: 726598
GnomAD4 genome AF: 0.0000658 AC: 10AN: 151954Hom.: 0 Cov.: 32 AF XY: 0.0000674 AC XY: 5AN XY: 74210
ClinVar
Submissions by phenotype
not provided Pathogenic:3
MME: PM3:Very Strong, PVS1, PM2 -
This sequence change creates a premature translational stop signal (p.Arg448*) in the MME gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in MME are known to be pathogenic (PMID: 26991897). This variant is present in population databases (rs149905705, gnomAD 0.03%). This premature translational stop signal has been observed in individuals with Charcot-Marie-Tooth disease or neutral endopeptidase deficiency (PMID: 15464186, 27588448, 30415211). ClinVar contains an entry for this variant (Variation ID: 504903). For these reasons, this variant has been classified as Pathogenic. -
Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 32657593, 25525159, 34426522, 31589614, 34480178, 34307994, 31429185, 35304567, 15800120, 26991897, 25565308, 15464186, 27588448, 30609409, 30415211) -
Congenital membranous nephropathy due to maternal anti-neutral endopeptidase alloimmunization Pathogenic:1
The p.Arg448X variant in MME has been reported in one compound heterozygote moth er with NEP deficiency who had a child with neonatal membranous glomerulopathy ( Debiec 2004). This variant has also been identified in 4/120,898 of chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs149905705). Although this variant has been seen in the general population, it s frequency is low enough to be consistent with a recessive carrier frequency. T his nonsense variant leads to a premature termination codon at position 448, whi ch is predicted to lead to a truncated or absent protein. Loss of function of th e MME gene in a mother is associated with fetomaternal alloimmunisation leading to fetal membranous glomerulopathy when a fetus has the normal MME gene copy. In summary, this variant meets our criteria to be classified as pathogenic for NEP deficiency (responsible for alloimmune antenatal membranous nephropathy) bas ed upon its co-occurrence with another disease-causing variant in an affected in dividual and the predicted functional impact. -
MME-related disorder Pathogenic:1
The MME c.1342C>T variant is predicted to result in premature protein termination (p.Arg448*). This variant was first reported in the compound heterozygous state in an individual with neutral endopeptidase deficiency who, in a retrospective study, developed Charcot-Marie-Tooth disease type 2 (CMT2, Debiec et al. 2004. PubMed ID: 15464186; Nortier et al. 2021. PubMed ID: 34307994). This variant has also been reported in the compound heterozygous or homozygous state in several unrelated individuals with CMT2 (Lupo et al. 2018. PubMed ID: 30415211), as well as autosomal recessive distal hereditary motor neuropathy (Hong et al. 2019. PubMed ID: 31429185). In addition, this variant has been reported in the heterozygous state in an individual with late-onset axonal neuropathies (individual US6/II-1 in Auer-Grumbach et al. 2016. PubMed ID: 27588448). In vitro functional studies using HEK293 cells demonstrated that expression of this variant results in significantly decreased mRNA levels and enzymatic activity (Hong et al. 2019. PubMed ID: 31429185). This variant is reported in 0.031% of alleles in individuals of Latino descent in gnomAD, and has been consistently interpreted as pathogenic by other laboratories in the ClinVar database (https://www.ncbi.nlm.nih.gov/clinvar/variation/504903/). Nonsense variants in MME are expected to be pathogenic. This variant is interpreted as pathogenic. -
Charcot-Marie-Tooth disease axonal type 2T;C4310763:Spinocerebellar ataxia 43 Pathogenic:1
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Spinocerebellar ataxia 43 Pathogenic:1
This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PVS1,PS1,PM1,PM2. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at