3-155084220-C-T

Variant names:

• chr3-155084220-C-T
• rs755684422
• NM_007289.4:c.53C>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. 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
• Publications: 0 publications found

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

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.25728154).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MME	NM_007289.4	c.53C>T	p.Pro18Leu	missense_variant	Exon 2 of 23	ENST00000360490.7	NP_009220.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MME	ENST00000360490.7	c.53C>T	p.Pro18Leu	missense_variant	Exon 2 of 23	1	NM_007289.4	ENSP00000353679.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.0000239 AC: 6 AN: 251474 AF XY: 0.0000221

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 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

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.0000894 AC: 4 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.0000108 AC: 12 AN: 1111970

Other (OTH) AF: 0.0000166 AC: 1 AN: 60394

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

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

Feb 28, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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
LIST_S2	Uncertain	0.92	.;D;.;D;D;.;.;.;.;D;D;D;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
PhyloP100		4.0
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
PromoterAI		-0.036	Neutral
Varity_R		0.099
gMVP		0.56
Mutation Taster		=61/39	polymorphism

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

Other links and lift over

dbSNP: rs755684422; hg19: chr3-154802009;