rs56208271

Variant names:

• chr3-155084043-G-A
• rs56208271
• NM_007289.4:c.-10-115G>A

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.-10-115G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.198 in 1,010,870 control chromosomes in the GnomAD database, including 22,896 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.17 (2578 hom., cov: 33)
  • Exomes 𝑓: 0.20 (20318 hom.)
• Consequence: MME NM_007289.4 intron
• Scores: Splicing: ADA: 0.00003835
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.28
• Publications: 2 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: AR, AD, SD 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: Labcorp Genetics (formerly Invitae), Orphanet, Ambry Genetics
• 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BP6: Variant 3-155084043-G-A is Benign according to our data. Variant chr3-155084043-G-A is described in ClinVar as Benign. ClinVar VariationId is 1279010.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.234 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MME	NM_007289.4	MANE Select	c.-10-115G>A		intron	N/A	NP_009220.2	P08473
	MME	NM_000902.5		c.-10-115G>A		intron	N/A	NP_000893.2	P08473
	MME	NM_001354642.2		c.-10-115G>A		intron	N/A	NP_001341571.1	P08473

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MME	ENST00000360490.7	TSL:1 MANE Select	c.-10-115G>A		intron	N/A	ENSP00000353679.2	P08473
	MME	ENST00000615825.2	TSL:1	c.-10-115G>A		intron	N/A	ENSP00000478173.2	A0A7I2U302
	MME	ENST00000460393.6	TSL:1	c.-10-115G>A		intron	N/A	ENSP00000418525.1	P08473

Frequencies

GnomAD3 genomes AF: 0.166 AC: 25258 AN: 152042 Hom.: 2578 Cov.: 33

Gnomad AFR AF: 0.0712

Gnomad AMI AF: 0.322

Gnomad AMR AF: 0.125

Gnomad ASJ AF: 0.194

Gnomad EAS AF: 0.0354

Gnomad SAS AF: 0.0548

Gnomad FIN AF: 0.235

Gnomad MID AF: 0.171

Gnomad NFE AF: 0.237

Gnomad OTH AF: 0.161

GnomAD4 exome AF: 0.204 AC: 175358 AN: 858710 Hom.: 20318 Cov.: 11 AF XY: 0.199 AC XY: 88304 AN XY: 442930

African (AFR) AF: 0.0634 AC: 1265 AN: 19966

American (AMR) AF: 0.0985 AC: 2980 AN: 30260

Ashkenazi Jewish (ASJ) AF: 0.194 AC: 3988 AN: 20536

East Asian (EAS) AF: 0.0449 AC: 1489 AN: 33130

South Asian (SAS) AF: 0.0610 AC: 3864 AN: 63368

European-Finnish (FIN) AF: 0.231 AC: 10480 AN: 45466

Middle Eastern (MID) AF: 0.114 AC: 329 AN: 2890

European-Non Finnish (NFE) AF: 0.238 AC: 143658 AN: 603328

Other (OTH) AF: 0.184 AC: 7305 AN: 39766

GnomAD4 genome AF: 0.166 AC: 25256 AN: 152160 Hom.: 2578 Cov.: 33 AF XY: 0.161 AC XY: 11990 AN XY: 74402

African (AFR) AF: 0.0709 AC: 2945 AN: 41516

American (AMR) AF: 0.125 AC: 1915 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.194 AC: 672 AN: 3472

East Asian (EAS) AF: 0.0353 AC: 183 AN: 5188

South Asian (SAS) AF: 0.0550 AC: 266 AN: 4832

European-Finnish (FIN) AF: 0.235 AC: 2487 AN: 10570

Middle Eastern (MID) AF: 0.177 AC: 52 AN: 294

European-Non Finnish (NFE) AF: 0.237 AC: 16104 AN: 67976

Other (OTH) AF: 0.160 AC: 338 AN: 2112

Alfa AF: 0.215 Hom.: 756

Bravo AF: 0.155

Asia WGS AF: 0.0560 AC: 197 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.42
DANN	Benign	0.27
PhyloP100		-1.3
PromoterAI		0.00040	Neutral
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000038
dbscSNV1_RF	Benign	0.082
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: rs56208271; hg19: chr3-154801832;