3-155083576-T-C

Variant names:

• chr3-155083576-T-C
• rs989692
• NM_007289.4:c.-10-582T>C

Variant summary

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

The NM_007289.4(MME):​c.-10-582T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.527 in 156,450 control chromosomes in the GnomAD database, including 22,381 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 0.53 (21769 hom., cov: 32)
  • Exomes 𝑓: 0.51 (612 hom.)
• Consequence: MME NM_007289.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.05
• Publications: 25 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=-0.74).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.773 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MME	NM_007289.4	c.-10-582T>C		intron_variant	Intron 1 of 22	ENST00000360490.7	NP_009220.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MME	ENST00000360490.7	c.-10-582T>C		intron_variant	Intron 1 of 22	1	NM_007289.4	ENSP00000353679.2

Frequencies

GnomAD3 genomes AF: 0.527 AC: 80076 AN: 151868 Hom.: 21764 Cov.: 32

Gnomad AFR AF: 0.433

Gnomad AMI AF: 0.342

Gnomad AMR AF: 0.559

Gnomad ASJ AF: 0.592

Gnomad EAS AF: 0.793

Gnomad SAS AF: 0.726

Gnomad FIN AF: 0.649

Gnomad MID AF: 0.620

Gnomad NFE AF: 0.522

Gnomad OTH AF: 0.556

GnomAD4 exome AF: 0.509 AC: 2273 AN: 4464 Hom.: 612 Cov.: 0 AF XY: 0.518 AC XY: 1260 AN XY: 2434

African (AFR) AF: 0.409 AC: 9 AN: 22

American (AMR) AF: 0.539 AC: 316 AN: 586

Ashkenazi Jewish (ASJ) AF: 0.389 AC: 7 AN: 18

East Asian (EAS) AF: 0.719 AC: 105 AN: 146

South Asian (SAS) AF: 0.711 AC: 236 AN: 332

European-Finnish (FIN) AF: 0.591 AC: 65 AN: 110

Middle Eastern (MID) AF: 0.500 AC: 1 AN: 2

European-Non Finnish (NFE) AF: 0.473 AC: 1448 AN: 3060

Other (OTH) AF: 0.457 AC: 86 AN: 188

GnomAD4 genome AF: 0.527 AC: 80109 AN: 151986 Hom.: 21769 Cov.: 32 AF XY: 0.538 AC XY: 40010 AN XY: 74318

African (AFR) AF: 0.433 AC: 17940 AN: 41438

American (AMR) AF: 0.559 AC: 8541 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.592 AC: 2054 AN: 3468

East Asian (EAS) AF: 0.793 AC: 4107 AN: 5176

South Asian (SAS) AF: 0.726 AC: 3504 AN: 4824

European-Finnish (FIN) AF: 0.649 AC: 6854 AN: 10562

Middle Eastern (MID) AF: 0.622 AC: 183 AN: 294

European-Non Finnish (NFE) AF: 0.522 AC: 35447 AN: 67938

Other (OTH) AF: 0.555 AC: 1167 AN: 2104

Alfa AF: 0.533 Hom.: 37500

Bravo AF: 0.513

Asia WGS AF: 0.721 AC: 2508 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.74
CADD	Benign	8.3
DANN	Benign	0.80
PhyloP100		-1.0
PromoterAI		0.0090	Neutral
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: rs989692; hg19: chr3-154801365;