NM_007289.4:c.2154-22A>G

Variant names:

• chr3-155180338-A-G
• rs16824656
• NM_007289.4:c.2154-22A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_007289.4(MME):​c.2154-22A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.087 in 1,589,878 control chromosomes in the GnomAD database, including 7,838 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). There are indicators that this mutation may affect the branch point..

• Frequency:
  • Genomes: 𝑓 0.12 (1431 hom., cov: 32)
  • Exomes 𝑓: 0.084 (6407 hom.)
• Consequence: MME NM_007289.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.977
• Publications: 4 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-AS1 (HGNC:40376): (MME antisense RNA 1)

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: This position, referring to a specific DNA site, is a probable branch point but is likely benign (scored 3 / 10, using the threshold of <=3). The score ranges from 0 to 10, with values ≤3 considered benign and >5 classified as pathogenic. Computational evidence support a benign effect (BayesDel_noAF=-0.64).
• BP6: Variant 3-155180338-A-G is Benign according to our data. Variant chr3-155180338-A-G is described in ClinVar as Benign. ClinVar VariationId is 1261728.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.197 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_007289.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MME	NM_007289.4	MANE Select	c.2154-22A>G		intron	N/A	NP_009220.2
	MME	NM_000902.5		c.2154-22A>G		intron	N/A	NP_000893.2
	MME	NM_001354642.2		c.2154-22A>G		intron	N/A	NP_001341571.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MME	ENST00000360490.7	TSL:1 MANE Select	c.2154-22A>G		intron	N/A	ENSP00000353679.2
	MME	ENST00000615825.2	TSL:1	c.2244-22A>G		intron	N/A	ENSP00000478173.2
	MME	ENST00000460393.6	TSL:1	c.2154-22A>G		intron	N/A	ENSP00000418525.1

Frequencies

GnomAD3 genomes AF: 0.117 AC: 17841 AN: 152056 Hom.: 1422 Cov.: 32

Gnomad AFR AF: 0.200

Gnomad AMI AF: 0.0110

Gnomad AMR AF: 0.0613

Gnomad ASJ AF: 0.0360

Gnomad EAS AF: 0.174

Gnomad SAS AF: 0.167

Gnomad FIN AF: 0.169

Gnomad MID AF: 0.0475

Gnomad NFE AF: 0.0703

Gnomad OTH AF: 0.0851

GnomAD2 exomes AF: 0.101 AC: 25237 AN: 250280 AF XY: 0.102

Gnomad AFR exome AF: 0.207

Gnomad AMR exome AF: 0.0465

Gnomad ASJ exome AF: 0.0369

Gnomad EAS exome AF: 0.179

Gnomad FIN exome AF: 0.160

Gnomad NFE exome AF: 0.0685

Gnomad OTH exome AF: 0.0809

GnomAD4 exome AF: 0.0838 AC: 120447 AN: 1437704 Hom.: 6407 Cov.: 27 AF XY: 0.0860 AC XY: 61669 AN XY: 716894

African (AFR) AF: 0.202 AC: 6641 AN: 32928

American (AMR) AF: 0.0500 AC: 2233 AN: 44664

Ashkenazi Jewish (ASJ) AF: 0.0367 AC: 951 AN: 25944

East Asian (EAS) AF: 0.202 AC: 7988 AN: 39574

South Asian (SAS) AF: 0.158 AC: 13537 AN: 85780

European-Finnish (FIN) AF: 0.156 AC: 8314 AN: 53382

Middle Eastern (MID) AF: 0.0456 AC: 260 AN: 5706

European-Non Finnish (NFE) AF: 0.0689 AC: 75124 AN: 1090198

Other (OTH) AF: 0.0907 AC: 5399 AN: 59528

GnomAD4 genome AF: 0.117 AC: 17872 AN: 152174 Hom.: 1431 Cov.: 32 AF XY: 0.122 AC XY: 9077 AN XY: 74398

African (AFR) AF: 0.201 AC: 8339 AN: 41526

American (AMR) AF: 0.0612 AC: 936 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.0360 AC: 125 AN: 3470

East Asian (EAS) AF: 0.174 AC: 898 AN: 5170

South Asian (SAS) AF: 0.167 AC: 805 AN: 4824

European-Finnish (FIN) AF: 0.169 AC: 1788 AN: 10590

Middle Eastern (MID) AF: 0.0442 AC: 13 AN: 294

European-Non Finnish (NFE) AF: 0.0703 AC: 4780 AN: 67994

Other (OTH) AF: 0.0842 AC: 178 AN: 2114

Alfa AF: 0.0865 Hom.: 385

Bravo AF: 0.111

Asia WGS AF: 0.163 AC: 564 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Jul 05, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.64
CADD	Benign	12
DANN	Benign	0.61
PhyloP100		-0.98
BranchPoint Hunter		3.0
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: rs16824656; hg19: chr3-154898127; COSMIC: COSV64707772;