3-155084189-A-G

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_007289.4(MME):c.22A>G(p.Met8Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0231 in 1,613,950 control chromosomes in the GnomAD database, including 525 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M8R) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.017 ( 33 hom., cov: 33)

Exomes 𝑓: 0.024 ( 492 hom. )

Consequence

MME
NM_007289.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 3.55

Publications

19 publications found

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 Gene-Disease associations (from GenCC):

Charcot-Marie-Tooth disease axonal type 2T
Inheritance: SD, AR, AD Classification: DEFINITIVE, STRONG, MODERATE, LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), ClinGen
MME-related autosomal dominant Charcot Marie Tooth disease type 2
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
spinocerebellar ataxia 43
Inheritance: AD Classification: SUPPORTIVE, LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), Orphanet
Charcot-Marie-Tooth disease type 2T
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
congenital membranous nephropathy due to maternal anti-neutral endopeptidase alloimmunization
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

MME links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.007651925).

BP6

Variant 3-155084189-A-G is Benign according to our data. Variant chr3-155084189-A-G is described in ClinVar as [Benign]. Clinvar id is 1221640.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0166 (2525/152306) while in subpopulation NFE AF = 0.0266 (1810/68028). AF 95% confidence interval is 0.0256. There are 33 homozygotes in GnomAd4. There are 1190 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 33 SD,AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MME	NM_007289.4 link	c.22A>G	p.Met8Val	missense_variant	Exon 2 of 23	ENST00000360490.7	NP_009220.2	P08473

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MME	ENST00000360490.7 link	c.22A>G	p.Met8Val	missense_variant	Exon 2 of 23	1	NM_007289.4	ENSP00000353679.2		P08473

Frequencies

GnomAD3 genomes

AF:

0.0166

AC:

2525

AN:

152188

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00495

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0143

Gnomad ASJ

AF:

0.00260

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.0110

Gnomad FIN

AF:

0.0187

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.0266

Gnomad OTH

AF:

0.0134

GnomAD2 exomes

AF:

0.0164

AC:

4119

AN:

251436

AF XY:

0.0171

show subpopulations

Gnomad AFR exome

AF:

0.00406

Gnomad AMR exome

AF:

0.0100

Gnomad ASJ exome

AF:

0.00218

Gnomad EAS exome

AF:

0.000109

Gnomad FIN exome

AF:

0.0218

Gnomad NFE exome

AF:

0.0244

Gnomad OTH exome

AF:

0.0210

GnomAD4 exome

AF:

0.0237

AC:

34696

AN:

1461644

Hom.:

492

Cov.:

AF XY:

0.0235

AC XY:

17116

AN XY:

727140

show subpopulations

African (AFR)

AF:

0.00382

AC:

128

AN:

33478

American (AMR)

AF:

0.0106

AC:

475

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00187

AC:

AN:

26136

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39694

South Asian (SAS)

AF:

0.0110

AC:

949

AN:

86254

European-Finnish (FIN)

AF:

0.0214

AC:

1144

AN:

53420

Middle Eastern (MID)

AF:

0.0137

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.0275

AC:

30581

AN:

1111786

Other (OTH)

AF:

0.0214

AC:

1290

AN:

60386

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.468

Heterozygous variant carriers

1568

3136

4703

6271

7839

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0166

AC:

2525

AN:

152306

Hom.:

Cov.:

AF XY:

0.0160

AC XY:

1190

AN XY:

74490

show subpopulations

African (AFR)

AF:

0.00493

AC:

205

AN:

41572

American (AMR)

AF:

0.0142

AC:

217

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.00260

AC:

AN:

3466

East Asian (EAS)

AF:

0.000193

AC:

AN:

5182

South Asian (SAS)

AF:

0.0112

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.0187

AC:

199

AN:

10616

Middle Eastern (MID)

AF:

0.00680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0266

AC:

1810

AN:

68028

Other (OTH)

AF:

0.0132

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

123

246

370

493

616

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0218

Hom.:

149

Bravo

AF:

0.0156

TwinsUK

AF:

0.0245

AC:

ALSPAC

AF:

0.0278

AC:

107

ESP6500AA

AF:

0.00590

AC:

ESP6500EA

AF:

0.0276

AC:

237

ExAC

AF:

0.0164

AC:

1990

Asia WGS

AF:

0.00462

AC:

AN:

3478

EpiCase

AF:

0.0250

EpiControl

AF:

0.0259

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 19, 2019

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

MME-related disorder

Benign:1

May 08, 2019

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.31

BayesDel_addAF

Benign

-0.21

BayesDel_noAF

Uncertain

-0.050

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.33

T;T;T;T;.;T;T;T;T;.;T;.;T;T

Eigen

Benign

0.16

Eigen_PC

Uncertain

0.28

FATHMM_MKL

Uncertain

0.88

LIST_S2

Uncertain

0.93

.;D;.;D;D;.;.;.;.;D;D;.;D;D

MetaRNN

Benign

0.0077

T;T;T;T;T;T;T;T;T;T;T;T;T;T

MetaSVM

Uncertain

-0.0083

MutationAssessor

Benign

0.90

L;.;L;.;.;.;L;L;L;.;.;.;.;L

PhyloP100

3.5

PrimateAI

Uncertain

0.67

PROVEAN

Benign

-0.88

N;.;N;N;.;D;N;N;N;N;N;D;N;.

REVEL

Uncertain

0.33

Sift

Uncertain

0.019

D;.;D;D;.;D;D;D;D;D;T;.;T;.

Sift4G

Benign

0.54

T;D;T;T;D;D;T;T;T;T;D;.;T;T

Polyphen

0.52

P;.;P;.;.;.;P;P;P;.;.;.;.;P

Vest4

0.72

MPC

0.12

ClinPred

0.0068

GERP RS

5.3

PromoterAI

-0.011

Neutral

(source)

Varity_R

0.33

gMVP

0.65

Mutation Taster

=94/6

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

Details are displayed if max score is > 0.2

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

Publications

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3-155084189-A-G

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over