rs749320057

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_007289.4(MME):c.467del(p.Pro156LeufsTer14) variant causes a frameshift change. The variant allele was found at a frequency of 0.000326 in 1,612,842 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.00041 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00032 ( 0 hom. )

Consequence

MME
NM_007289.4 frameshift

Scores

Not classified

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:14O:1

Conservation

PhyloP100: 7.20

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 3-155116689-AC-A is Pathogenic according to our data. Variant chr3-155116689-AC-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 426945.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-155116689-AC-A is described in Lovd as [Likely_pathogenic]. Variant chr3-155116689-AC-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MME	NM_007289.4 linkuse as main transcript	c.467del	p.Pro156LeufsTer14	frameshift_variant	6/23	ENST00000360490.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MME	ENST00000360490.7 linkuse as main transcript	c.467del	p.Pro156LeufsTer14	frameshift_variant	6/23	1	NM_007289.4	P1

Frequencies

GnomAD3 genomes

AF:

0.000408

AC:

AN:

151872

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000725

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00257

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:

0.000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000260

AC:

AN:

250084

Hom.:

AF XY:

0.000214

AC XY:

AN XY:

135422

show subpopulations

Gnomad AFR exome

AF:

0.000127

Gnomad AMR exome

AF:

0.000726

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000462

Gnomad NFE exome

AF:

0.000327

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000318

AC:

464

AN:

1460970

Hom.:

Cov.:

AF XY:

0.000307

AC XY:

223

AN XY:

726690

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000515

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000562

Gnomad4 NFE exome

AF:

0.000384

Gnomad4 OTH exome

AF:

0.000182

GnomAD4 genome

AF:

0.000408

AC:

AN:

151872

Hom.:

Cov.:

AF XY:

0.000485

AC XY:

AN XY:

74156

show subpopulations

Gnomad4 AFR

AF:

0.0000725

Gnomad4 AMR

AF:

0.00257

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000294

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000218

Hom.:

Bravo

AF:

0.000427

EpiCase

AF:

0.000328

EpiControl

AF:

0.000119

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:14Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:7

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 25, 2024	This sequence change creates a premature translational stop signal (p.Pro156Leufs*14) 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 (rs749320057, gnomAD 0.07%). This premature translational stop signal has been observed in individual(s) with late-onset axonal Charcot-Marie-Tooth disease, and alloimmune antenatal membranous nephropathy (PMID: 15464186, 25565308, 27588448). ClinVar contains an entry for this variant (Variation ID: 426945). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Apr 27, 2022	Reported to segregate with disease in two unrelated families with autosomal dominant late-onset peripheral neuropathy (Auer-Grumbach et al., 2016); Frameshift 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: 25565308, 34758253, 15464186, 27588448, 30415211, 31974930, 34307994, 31589614, 33726816, 32345996, 31429185, 20692264, 35318247) -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Sep 15, 2021	- -
Likely pathogenic, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2023	MME: PVS1, PP1:Moderate -
Likely pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics and Genomics, Karolinska University Hospital	Jun 30, 2017	- -
Likely pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

Charcot-Marie-Tooth disease axonal type 2T

Pathogenic:5Other:1

Pathogenic, no assertion criteria provided	clinical testing	Genomics England Pilot Project, Genomics England	-	- -
risk factor, no assertion criteria provided	literature only	OMIM	Oct 06, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Apr 27, 2022	_x000D_ Criteria applied: PVS1, PS4_SUP, PP1 -
Pathogenic, criteria provided, single submitter	clinical testing	MGZ Medical Genetics Center	Jun 08, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	3billion	May 22, 2022	The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.025%). Frameshift: predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant. The variant has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000426945 / PMID: 15464186 / 3billion dataset). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jan 15, 2024	Variant summary: MME c.467delC (p.Pro156LeufsX14) results in a premature termination codon, predicted to cause absence of the protein due to nonsense mediated decay, which is a commonly known mechanism for disease. The variant allele was found at a frequency of 0.00026 in 250084 control chromosomes (gnomAD). c.467delC has been reported in the literature in multiple individuals affected with Charcot-Marie Disease Axonal Type 2T (Hoyer_2022). These data indicate that the variant is very likely to be associated with disease. The following publication has been ascertained in the context of this evaluation (PMID: 35318247). ClinVar contains an entry for this variant (Variation ID: 426945). Based on the evidence outlined above, the variant was classified as pathogenic. -

Charcot-Marie-Tooth disease type 2T

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Molecular Genetics, Royal Melbourne Hospital

Jun 15, 2023

This sequence change in MME is a frameshift variant predicted to cause a premature stop codon, p.(Pro156Leufs*14), in biologically relevant exon 6/23 leading to nonsense-mediated decay in a gene in which loss of function is an established disease mechanism (PMID: 33144514, 27588448). The highest population minor allele frequency in the population database gnomAD v2.1 is 0.07% (25/35,256 alleles) in the Latino/Admixed American population. This variant has been reported in the context of both recessive and dominant (dominant risk factor with incomplete penetrance) inheritance patterns for Charcot-Marie-Tooth (CMT) disease (PMID: 33144514). The variant has been reported to segregate with CMT in multiple families with evidence for semi-dominant inheritance (PMID: 27588448, 33144514, 35318247). A significant reduction in neprilysin levels has been reported in the adipose tissue and blood plasma of heterozygous carriers compared to controls (PMID: 27588448). Based on the classification scheme RMH Modified ACMG Guidelines v1.5.1, this variant is classified as PATHOGENIC. Following criteria are met: PVS1, PP1_Strong. -

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,PM1,PP5. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

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