3-155084189-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_007289.4(MME):c.22A>G(p.Met8Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0231 in 1,613,950 control chromosomes in the GnomAD database, including 525 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.017 (33 hom., cov: 33)
  • Exomes 𝑓: 0.024 (492 hom.)
• Consequence: MME NM_007289.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 3.55

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.007651925).
• BP6: Variant 3-155084189-A-G is Benign according to our data. Variant chr3-155084189-A-G is described in ClinVar as [Benign]. Clinvar id is 1221640.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-155084189-A-G is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0166 (2525/152306) while in subpopulation NFE AF= 0.0266 (1810/68028). AF 95% confidence interval is 0.0256. There are 33 homozygotes in gnomad4. There are 1190 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 33 SD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MME	NM_007289.4	c.22A>G	p.Met8Val	missense_variant	2/23	ENST00000360490.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MME	ENST00000360490.7	c.22A>G	p.Met8Val	missense_variant	2/23	1	NM_007289.4	P1

Frequencies

GnomAD3 genomes AF: 0.0166 AC: 2525 AN: 152188 Hom.: 33 Cov.: 33

Gnomad AFR AF: 0.00495

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0143

Gnomad ASJ AF: 0.00260

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.0110

Gnomad FIN AF: 0.0187

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0266

Gnomad OTH AF: 0.0134

GnomAD3 exomes AF: 0.0164 AC: 4119 AN: 251436 Hom.: 48 AF XY: 0.0171 AC XY: 2324 AN XY: 135896

Gnomad AFR exome AF: 0.00406

Gnomad AMR exome AF: 0.0100

Gnomad ASJ exome AF: 0.00218

Gnomad EAS exome AF: 0.000109

Gnomad SAS exome AF: 0.0101

Gnomad FIN exome AF: 0.0218

Gnomad NFE exome AF: 0.0244

Gnomad OTH exome AF: 0.0210

GnomAD4 exome AF: 0.0237 AC: 34696 AN: 1461644 Hom.: 492 Cov.: 31 AF XY: 0.0235 AC XY: 17116 AN XY: 727140

Gnomad4 AFR exome AF: 0.00382

Gnomad4 AMR exome AF: 0.0106

Gnomad4 ASJ exome AF: 0.00187

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0110

Gnomad4 FIN exome AF: 0.0214

Gnomad4 NFE exome AF: 0.0275

Gnomad4 OTH exome AF: 0.0214

GnomAD4 genome AF: 0.0166 AC: 2525 AN: 152306 Hom.: 33 Cov.: 33 AF XY: 0.0160 AC XY: 1190 AN XY: 74490

Gnomad4 AFR AF: 0.00493

Gnomad4 AMR AF: 0.0142

Gnomad4 ASJ AF: 0.00260

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.0112

Gnomad4 FIN AF: 0.0187

Gnomad4 NFE AF: 0.0266

Gnomad4 OTH AF: 0.0132

Alfa AF: 0.0221 Hom.: 75

Bravo AF: 0.0156

TwinsUK AF: 0.0245 AC: 91

ALSPAC AF: 0.0278 AC: 107

ESP6500AA AF: 0.00590 AC: 26

ESP6500EA AF: 0.0276 AC: 237

ExAC AF: 0.0164 AC: 1990

Asia WGS AF: 0.00462 AC: 16 AN: 3478

EpiCase AF: 0.0250

EpiControl AF: 0.0259

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 19, 2019	- -

MME-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

May 08, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.31
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Uncertain	-0.050
Cadd	Benign	22
Dann	Uncertain	0.99
DEOGEN2	Benign	0.33	T;T;T;T;.;T;T;T;T;.;T;.;T;T
Eigen	Benign	0.16
Eigen_PC	Uncertain	0.28
FATHMM_MKL	Uncertain	0.88	D
MetaRNN	Benign	0.0077	T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	-0.0083	T
MutationAssessor	Benign	0.90	L;.;L;.;.;.;L;L;L;.;.;.;.;L
MutationTaster	Benign	0.98	D;D;D;D;D;D
PrimateAI	Uncertain	0.67	T
PROVEAN	Benign	-0.88	N;.;N;N;.;D;N;N;N;N;N;D;N;.
REVEL	Uncertain	0.33
Sift	Uncertain	0.019	D;.;D;D;.;D;D;D;D;D;T;.;T;.
Sift4G	Benign	0.54	T;D;T;T;D;D;T;T;T;T;D;.;T;T
Polyphen		0.52	P;.;P;.;.;.;P;P;P;.;.;.;.;P
Vest4		0.72
MPC		0.12
ClinPred		0.0068	T
GERP RS		5.3
Varity_R		0.33
gMVP		0.65

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs61762319; hg19: chr3-154801978;