rs9827586

Variant names:

• chr3-155107596-G-A
• rs9827586
• NM_007289.4:c.197-7398G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_007289.4(MME):​c.197-7398G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.325 in 151,960 control chromosomes in the GnomAD database, including 8,669 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.33 (8669 hom., cov: 31)
• Consequence: MME NM_007289.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0110
• Publications: 6 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.96).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.406 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MME	NM_007289.4	c.197-7398G>A		intron_variant	Intron 3 of 22	ENST00000360490.7	NP_009220.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MME	ENST00000360490.7	c.197-7398G>A		intron_variant	Intron 3 of 22	1	NM_007289.4	ENSP00000353679.2

Frequencies

GnomAD3 genomes AF: 0.325 AC: 49424 AN: 151844 Hom.: 8669 Cov.: 31

Gnomad AFR AF: 0.235

Gnomad AMI AF: 0.500

Gnomad AMR AF: 0.252

Gnomad ASJ AF: 0.340

Gnomad EAS AF: 0.140

Gnomad SAS AF: 0.190

Gnomad FIN AF: 0.375

Gnomad MID AF: 0.334

Gnomad NFE AF: 0.410

Gnomad OTH AF: 0.310

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.325 AC: 49429 AN: 151960 Hom.: 8669 Cov.: 31 AF XY: 0.317 AC XY: 23565 AN XY: 74254

African (AFR) AF: 0.235 AC: 9749 AN: 41462

American (AMR) AF: 0.252 AC: 3848 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.340 AC: 1178 AN: 3468

East Asian (EAS) AF: 0.140 AC: 723 AN: 5168

South Asian (SAS) AF: 0.189 AC: 914 AN: 4824

European-Finnish (FIN) AF: 0.375 AC: 3943 AN: 10518

Middle Eastern (MID) AF: 0.345 AC: 100 AN: 290

European-Non Finnish (NFE) AF: 0.410 AC: 27866 AN: 67938

Other (OTH) AF: 0.309 AC: 653 AN: 2112

Alfa AF: 0.373 Hom.: 28183

Bravo AF: 0.315

Asia WGS AF: 0.200 AC: 696 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.96
CADD	Benign	0.43
DANN	Benign	0.62
PhyloP100		0.011
Mutation Taster		=100/0	polymorphism (auto)

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: rs9827586; hg19: chr3-154825385;