3-155084192-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_007289.4(MME):c.25G>A(p.Asp9Asn) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D9G) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: MME NM_007289.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.34

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MME	NM_007289.4	c.25G>A	p.Asp9Asn	missense_variant	2/23	ENST00000360490.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MME	ENST00000360490.7	c.25G>A	p.Asp9Asn	missense_variant	2/23	1	NM_007289.4	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Oct 18, 2022

This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 9 of the MME protein (p.Asp9Asn). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with MME-related conditions. ClinVar contains an entry for this variant (Variation ID: 1470627). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.34
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Uncertain	-0.080
Cadd	Pathogenic	26
Dann	Pathogenic	1.0
DEOGEN2	Benign	0.39	T;T;T;T;.;T;T;T;T;.;T;.;T;T
Eigen	Uncertain	0.54
Eigen_PC	Uncertain	0.57
FATHMM_MKL	Uncertain	0.88	D
M_CAP	Benign	0.082	D
MetaRNN	Uncertain	0.43	T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	0.57	D
MutationAssessor	Benign	1.2	L;.;L;.;.;.;L;L;L;.;.;.;.;L
MutationTaster	Benign	1.0	D;D;D;D;D;D
PrimateAI	Pathogenic	0.79	T
PROVEAN	Benign	-1.5	N;.;N;N;.;D;N;N;N;N;N;D;N;.
REVEL	Uncertain	0.36
Sift	Benign	0.055	T;.;T;D;.;D;T;T;T;D;T;.;D;.
Sift4G	Benign	0.38	T;D;T;T;D;D;T;T;T;T;D;.;T;T
Polyphen		0.99	D;.;D;.;.;.;D;D;D;.;.;.;.;D
Vest4		0.43
MutPred		0.34		Gain of sheet (P = 0.0477);Gain of sheet (P = 0.0477);Gain of sheet (P = 0.0477);Gain of sheet (P = 0.0477);Gain of sheet (P = 0.0477);Gain of sheet (P = 0.0477);Gain of sheet (P = 0.0477);Gain of sheet (P = 0.0477);Gain of sheet (P = 0.0477);Gain of sheet (P = 0.0477);Gain of sheet (P = 0.0477);Gain of sheet (P = 0.0477);Gain of sheet (P = 0.0477);Gain of sheet (P = 0.0477);
MVP		0.95
MPC		0.14
ClinPred		0.90	D
GERP RS		5.3
Varity_R		0.13
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

No publications associated with this variant yet.

Other links and lift over

hg19: chr3-154801981; COSMIC: COSV100852317;