rs879253751

Variant names:

• chr3-155118752-C-G
• rs879253751
• NM_007289.4:c.661C>G

Your query was ambiguous. Multiple possible variants found:

• chr3-155118752-C-G
• chr3-155118752-C-T

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_007289.4(MME):​c.661C>G​(p.Gln221Glu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000695 in 1,439,714 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: MME NM_007289.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.53
• Publications: 1 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_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.977

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MME	NM_007289.4	c.661C>G	p.Gln221Glu	missense_variant	Exon 8 of 23	ENST00000360490.7	NP_009220.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MME	ENST00000360490.7	c.661C>G	p.Gln221Glu	missense_variant	Exon 8 of 23	1	NM_007289.4	ENSP00000353679.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000412 AC: 1 AN: 242612 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000294

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.95e-7 AC: 1 AN: 1439714 Hom.: 0 Cov.: 27 AF XY: 0.00 AC XY: 0 AN XY: 717116

African (AFR) AF: 0.00 AC: 0 AN: 32858

American (AMR) AF: 0.0000226 AC: 1 AN: 44290

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25850

East Asian (EAS) AF: 0.00 AC: 0 AN: 39352

South Asian (SAS) AF: 0.00 AC: 0 AN: 85048

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53026

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5698

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1094046

Other (OTH) AF: 0.00 AC: 0 AN: 59546

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.27
BayesDel_addAF	Pathogenic	0.32	D
BayesDel_noAF	Pathogenic	0.30
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.84	D;D;T;D;D;D;D
Eigen	Pathogenic	0.78
Eigen_PC	Pathogenic	0.77
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.97	.;.;D;.;.;.;D
M_CAP	Benign	0.073	D
MetaRNN	Pathogenic	0.98	D;D;D;D;D;D;D
MetaSVM	Uncertain	0.26	D
MutationAssessor	Uncertain	2.4	M;M;.;M;M;M;M
PhyloP100		7.5
PrimateAI	Benign	0.43	T
PROVEAN	Uncertain	-2.8	D;D;D;D;D;D;.
REVEL	Pathogenic	0.83
Sift	Pathogenic	0.0	D;D;D;D;D;D;.
Sift4G	Uncertain	0.019	D;D;T;D;D;D;D
Polyphen		0.99	D;D;.;D;D;D;D
Vest4		0.91
MutPred		0.92		Gain of catalytic residue at Q221 (P = 0.0631);Gain of catalytic residue at Q221 (P = 0.0631);Gain of catalytic residue at Q221 (P = 0.0631);Gain of catalytic residue at Q221 (P = 0.0631);Gain of catalytic residue at Q221 (P = 0.0631);Gain of catalytic residue at Q221 (P = 0.0631);Gain of catalytic residue at Q221 (P = 0.0631);
MVP		0.88
MPC		0.40
ClinPred		0.87	D
GERP RS		5.5
Varity_R		0.94
gMVP		0.78
Mutation Taster		=63/37	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: rs879253751; hg19: chr3-154836541;