3-155160423-T-A

Position:

• chr3-155160423-T-A

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_007289.4(MME):​c.1635T>A​(p.Phe545Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000687 in 1,456,162 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: MME NM_007289.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.65

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-AS1 (HGNC:40376): (MME antisense RNA 1)

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.979

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MME	NM_007289.4	c.1635T>A	p.Phe545Leu	missense_variant	17/23	ENST00000360490.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MME	ENST00000360490.7	c.1635T>A	p.Phe545Leu	missense_variant	17/23	1	NM_007289.4	P1
MME-AS1	ENST00000484721.2	n.215-1440A>T		intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.87e-7 AC: 1 AN: 1456162 Hom.: 0 Cov.: 28 AF XY: 0.00000138 AC XY: 1 AN XY: 724774

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

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: 9.03e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

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

Labcorp Genetics (formerly Invitae), Labcorp

Mar 29, 2022

This variant is not present in population databases (gnomAD no frequency). This sequence change replaces phenylalanine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 545 of the MME protein (p.Phe545Leu). This variant has not been reported in the literature in individuals affected with MME-related conditions. 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: "Probably Damaging"; Align-GVGD: "Class C0"). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.39	D
BayesDel_noAF	Pathogenic	0.32
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.90	D;D;D;D;D;D
Eigen	Uncertain	0.55
Eigen_PC	Uncertain	0.46
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.93	.;.;.;.;.;D
M_CAP	Uncertain	0.22	D
MetaRNN	Pathogenic	0.98	D;D;D;D;D;D
MetaSVM	Uncertain	0.38	D
MutationAssessor	Uncertain	2.7	M;M;M;M;M;M
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Pathogenic	0.84	D
PROVEAN	Pathogenic	-5.2	D;D;D;D;D;.
REVEL	Pathogenic	0.88
Sift	Uncertain	0.0030	D;D;D;D;D;.
Sift4G	Uncertain	0.0050	D;D;D;D;D;D
Polyphen		1.0	D;D;D;D;D;D
Vest4		0.91
MutPred		0.90		Loss of stability (P = 0.0412);Loss of stability (P = 0.0412);Loss of stability (P = 0.0412);Loss of stability (P = 0.0412);Loss of stability (P = 0.0412);Loss of stability (P = 0.0412);
MVP		0.90
MPC		0.42
ClinPred		1.0	D
GERP RS		3.2
Varity_R		0.86
gMVP		0.80

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: rs1223528672; hg19: chr3-154878212;