NM_007289.4:c.-10-17A>G

Variant names:

• chr3-155084141-A-G
• rs148774018
• NM_007289.4:c.-10-17A>G

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_007289.4(MME):​c.-10-17A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000314 in 1,594,296 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0017 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00017 (2 hom.)
• Consequence: MME NM_007289.4 intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.59
• 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: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.93).
• BP6: Variant 3-155084141-A-G is Benign according to our data. Variant chr3-155084141-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 1193895.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00172 (262/152234) while in subpopulation AFR AF = 0.00611 (254/41546). AF 95% confidence interval is 0.0055. There are 0 homozygotes in GnomAd4. There are 131 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 2 SD,AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MME	NM_007289.4	c.-10-17A>G		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.-10-17A>G		intron_variant	Intron 1 of 22	1	NM_007289.4	ENSP00000353679.2

Frequencies

GnomAD3 genomes AF: 0.00172 AC: 262 AN: 152116 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00613

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.000958

GnomAD2 exomes AF: 0.000483 AC: 121 AN: 250688 AF XY: 0.000346

Gnomad AFR exome AF: 0.00694

Gnomad AMR exome AF: 0.000174

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: 0.000327

GnomAD4 exome AF: 0.000166 AC: 239 AN: 1442062 Hom.: 2 Cov.: 27 AF XY: 0.000135 AC XY: 97 AN XY: 718822

African (AFR) AF: 0.00617 AC: 204 AN: 33078

American (AMR) AF: 0.000157 AC: 7 AN: 44694

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25996

East Asian (EAS) AF: 0.00 AC: 0 AN: 39612

South Asian (SAS) AF: 0.00 AC: 0 AN: 85730

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53350

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5716

European-Non Finnish (NFE) AF: 0.0000110 AC: 12 AN: 1094134

Other (OTH) AF: 0.000268 AC: 16 AN: 59752

GnomAD4 genome AF: 0.00172 AC: 262 AN: 152234 Hom.: 0 Cov.: 33 AF XY: 0.00176 AC XY: 131 AN XY: 74420

African (AFR) AF: 0.00611 AC: 254 AN: 41546

American (AMR) AF: 0.000262 AC: 4 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10598

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68010

Other (OTH) AF: 0.000948 AC: 2 AN: 2110

Alfa AF: 0.000928 Hom.: 0

Bravo AF: 0.00187

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Oct 18, 2020

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	0.039
DANN	Benign	0.45
PhyloP100		-1.6
PromoterAI		-0.0028	Neutral
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs148774018; hg19: chr3-154801930;