3-155084220-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_007289.4(MME):c.53C>T(p.Pro18Leu) variant causes a missense change. The variant allele was found at a frequency of 0.0000116 in 1,461,846 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: not found (cov: 33)
  • Exomes 𝑓: 0.000012 (0 hom.)
• Consequence: MME NM_007289.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.96

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.25728154).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MME	NM_007289.4	c.53C>T	p.Pro18Leu	missense_variant	2/23	ENST00000360490.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MME	ENST00000360490.7	c.53C>T	p.Pro18Leu	missense_variant	2/23	1	NM_007289.4	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.0000239 AC: 6 AN: 251474 Hom.: 0 AF XY: 0.0000221 AC XY: 3 AN XY: 135910

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000867

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: 0.0000176

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.0000116 AC: 17 AN: 1461846 Hom.: 0 Cov.: 31 AF XY: 0.0000179 AC XY: 13 AN XY: 727230

Gnomad4 AFR exome AF: 0.00

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: 0.0000108

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 33

ExAC AF: 0.0000247 AC: 3

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

Feb 28, 2022

This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 18 of the MME protein (p.Pro18Leu). 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. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals affected with MME-related conditions. This variant is present in population databases (rs755684422, gnomAD 0.006%). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.089
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Uncertain	0.13
Cadd	Benign	23
Dann	Uncertain	0.99
DEOGEN2	Uncertain	0.47	T;T;T;T;.;T;T;T;T;.;T;T;T
Eigen	Benign	-0.047
Eigen_PC	Benign	0.16
FATHMM_MKL	Uncertain	0.89	D
M_CAP	Benign	0.034	D
MetaRNN	Benign	0.26	T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	-0.095	T
MutationAssessor	Benign	1.6	L;.;L;.;.;.;L;L;L;.;.;.;L
MutationTaster	Benign	1.0	D;D;D;D;D;D
PrimateAI	Uncertain	0.56	T
PROVEAN	Benign	-1.6	N;.;N;N;.;D;N;N;N;D;D;N;.
REVEL	Uncertain	0.43
Sift	Uncertain	0.013	D;.;D;D;.;D;D;D;D;D;D;T;.
Sift4G	Benign	0.35	T;D;T;T;D;D;T;T;T;T;D;T;T
Polyphen		0.0	B;.;B;.;.;.;B;B;B;.;.;.;B
Vest4		0.66
MutPred		0.32		Loss of glycosylation at P18 (P = 0.005);Loss of glycosylation at P18 (P = 0.005);Loss of glycosylation at P18 (P = 0.005);Loss of glycosylation at P18 (P = 0.005);Loss of glycosylation at P18 (P = 0.005);Loss of glycosylation at P18 (P = 0.005);Loss of glycosylation at P18 (P = 0.005);Loss of glycosylation at P18 (P = 0.005);Loss of glycosylation at P18 (P = 0.005);Loss of glycosylation at P18 (P = 0.005);Loss of glycosylation at P18 (P = 0.005);Loss of glycosylation at P18 (P = 0.005);Loss of glycosylation at P18 (P = 0.005);
MVP		0.93
MPC		0.065
ClinPred		0.30	T
GERP RS		5.3
Varity_R		0.099
gMVP		0.56

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

Other links and lift over

dbSNP: rs755684422; hg19: chr3-154802009;