3-155084214-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_007289.4(MME):c.47C>A(p.Pro16Gln) variant causes a missense change. The variant allele was found at a frequency of 0.000044 in 1,613,936 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.00012 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000036 ( 0 hom. )

Consequence

MME
NM_007289.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:3

Conservation

PhyloP100: 4.02

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 Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.25133908).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MME	NM_007289.4 linkuse as main transcript	c.47C>A	p.Pro16Gln	missense_variant	2/23	ENST00000360490.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MME	ENST00000360490.7 linkuse as main transcript	c.47C>A	p.Pro16Gln	missense_variant	2/23	1	NM_007289.4	P1

Frequencies

GnomAD3 genomes

AF:

0.000125

AC:

AN:

152078

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000590

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:

0.000132

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000398

AC:

AN:

251476

Hom.:

AF XY:

0.0000515

AC XY:

AN XY:

135914

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000703

Gnomad OTH exome

AF:

0.000326

GnomAD4 exome

AF:

0.0000356

AC:

AN:

1461858

Hom.:

Cov.:

AF XY:

0.0000371

AC XY:

AN XY:

727228

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.0000894

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000378

Gnomad4 OTH exome

AF:

0.0000828

GnomAD4 genome

AF:

0.000125

AC:

AN:

152078

Hom.:

Cov.:

AF XY:

0.000121

AC XY:

AN XY:

74272

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.000590

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000132

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000113

Hom.:

Bravo

AF:

0.000117

ExAC

AF:

0.0000247

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Aug 04, 2023	In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 1305169). This variant has not been reported in the literature in individuals affected with MME-related conditions. This variant is present in population databases (rs199935778, gnomAD 0.009%). This sequence change replaces proline, which is neutral and non-polar, with glutamine, which is neutral and polar, at codon 16 of the MME protein (p.Pro16Gln). -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Apr 12, 2019	In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Has not been previously published as pathogenic or benign to our knowledge -

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 16, 2024

The c.47C>A (p.P16Q) alteration is located in exon 2 (coding exon 1) of the MME gene. This alteration results from a C to A substitution at nucleotide position 47, causing the proline (P) at amino acid position 16 to be replaced by a glutamine (Q). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.080

BayesDel_addAF

Uncertain

0.13

BayesDel_noAF

Pathogenic

0.14

Cadd

Benign

Dann

Uncertain

0.99

DEOGEN2

Benign

0.29

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

Eigen

Uncertain

0.20

Eigen_PC

Uncertain

0.28

FATHMM_MKL

Uncertain

0.91

M_CAP

Benign

0.060

MetaRNN

Benign

0.25

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

MetaSVM

Uncertain

0.22

MutationAssessor

Uncertain

2.2

M;.;M;.;.;.;M;M;M;.;.;.;M

MutationTaster

Benign

0.94

D;D;D;D;D;D

PrimateAI

Uncertain

0.50

PROVEAN

Benign

-0.63

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

REVEL

Uncertain

0.42

Sift

Uncertain

0.029

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

Sift4G

Benign

0.58

T;D;T;T;D;D;T;T;T;T;T;T;T

Polyphen

0.87

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

Vest4

0.39

MutPred

0.23

Loss of glycosylation at P16 (P = 0.0079);Loss of glycosylation at P16 (P = 0.0079);Loss of glycosylation at P16 (P = 0.0079);Loss of glycosylation at P16 (P = 0.0079);Loss of glycosylation at P16 (P = 0.0079);Loss of glycosylation at P16 (P = 0.0079);Loss of glycosylation at P16 (P = 0.0079);Loss of glycosylation at P16 (P = 0.0079);Loss of glycosylation at P16 (P = 0.0079);Loss of glycosylation at P16 (P = 0.0079);Loss of glycosylation at P16 (P = 0.0079);Loss of glycosylation at P16 (P = 0.0079);Loss of glycosylation at P16 (P = 0.0079);

MVP

0.93

MPC

0.23

ClinPred

0.20

GERP RS

4.4

Varity_R

0.088

gMVP

0.55

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