chr3-155144383-C-T

Position:

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.Arg448Ter) 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

Genomes: 𝑓 0.000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000072 ( 0 hom. )

Consequence

MME
NM_007289.4 stop_gained

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:5

Conservation

PhyloP100: 4.13

Variant links:

Genes affected

MME (HGNC:7154): (membrane metalloendopeptidase) The protein encoded by this gene is a type II transmembrane glycoprotein and a common acute lymphocytic leukemia antigen that is an important cell surface marker in the diagnosis of human acute lymphocytic leukemia (ALL). The encoded protein is present on leukemic cells of pre-B phenotype, which represent 85% of cases of ALL. This protein is not restricted to leukemic cells, however, and is found on a variety of normal tissues. The protein is a neutral endopeptidase that cleaves peptides at the amino side of hydrophobic residues and inactivates several peptide hormones including glucagon, enkephalins, substance P, neurotensin, oxytocin, and bradykinin. [provided by RefSeq, Aug 2017]

MME links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 18 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 3-155144383-C-T is Pathogenic according to our data. Variant chr3-155144383-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 504903.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-155144383-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MME	NM_007289.4 linkuse as main transcript	c.1342C>T	p.Arg448Ter	stop_gained	14/23	ENST00000360490.7	NP_009220.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MME	ENST00000360490.7 linkuse as main transcript	c.1342C>T	p.Arg448Ter	stop_gained	14/23	1	NM_007289.4	ENSP00000353679	P1

Frequencies

GnomAD3 genomes

AF:

0.0000658

AC:

AN:

151954

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000725

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000657

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000735

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.0000798

AC:

AN:

250696

Hom.:

AF XY:

0.0000812

AC XY:

AN XY:

135490

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000319

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000707

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000719

AC:

105

AN:

1460430

Hom.:

Cov.:

AF XY:

0.0000757

AC XY:

AN XY:

726598

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.000336

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000253

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000765

Gnomad4 OTH exome

AF:

0.0000497

GnomAD4 genome

AF:

0.0000658

AC:

AN:

151954

Hom.:

Cov.:

AF XY:

0.0000674

AC XY:

AN XY:

74210

show subpopulations

Gnomad4 AFR

AF:

0.0000725

Gnomad4 AMR

AF:

0.0000657

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000735

Gnomad4 OTH

AF:

0.000478

Alfa

AF:

0.0000920

Hom.:

Bravo

AF:

0.0000945

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.0000330

AC:

EpiCase

AF:

0.0000546

EpiControl

AF:

0.000178

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	May 19, 2022	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) -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 25, 2024	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. -

MME-related disorder

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 21, 2024

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. -

Congenital membranous nephropathy due to maternal anti-neutral endopeptidase alloimmunization

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Mar 28, 2016

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. -

Spinocerebellar ataxia 43

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Nov 14, 2019

This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PVS1,PS1,PM1,PM2. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.41

BayesDel_noAF

Pathogenic

0.66

CADD

Pathogenic

DANN

Uncertain

1.0

Eigen

Pathogenic

0.91

Eigen_PC

Pathogenic

0.81

FATHMM_MKL

Pathogenic

0.97

MutationTaster

Benign

1.0

A;A;A;A;A

Vest4

0.99

GERP RS

5.9

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over