chr3-155116689-AC-A

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PVS1PP5_Very_Strong

The NM_007289.4(MME):c.467delC(p.Pro156LeufsTer14) variant causes a frameshift change. The variant allele was found at a frequency of 0.000326 in 1,612,842 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.00041 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00032 ( 0 hom. )

Consequence

MME
NM_007289.4 frameshift

Scores

Not classified

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:18O:1

Conservation

PhyloP100: 7.20

Publications

10 publications found

Variant links:

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: AD, AR, SD Classification: DEFINITIVE, STRONG, MODERATE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, 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, Orphanet, Labcorp Genetics (formerly Invitae)
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

MME links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 16 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PP5

Variant 3-155116689-AC-A is Pathogenic according to our data. Variant chr3-155116689-AC-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 426945.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
MME	NM_007289.4	MANE Select	c.467delC	p.Pro156LeufsTer14	frameshift	Exon 6 of 23	NP_009220.2	P08473
MME	NM_000902.5		c.467delC	p.Pro156LeufsTer14	frameshift	Exon 6 of 23	NP_000893.2	P08473
MME	NM_001354642.2		c.467delC	p.Pro156LeufsTer14	frameshift	Exon 6 of 23	NP_001341571.1	P08473

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
MME	ENST00000360490.7	TSL:1 MANE Select	c.467delC	p.Pro156LeufsTer14	frameshift	Exon 6 of 23	ENSP00000353679.2	P08473
MME	ENST00000615825.2	TSL:1	c.467delC	p.Pro156LeufsTer14	frameshift	Exon 6 of 24	ENSP00000478173.2	A0A7I2U302
MME	ENST00000460393.6	TSL:1	c.467delC	p.Pro156LeufsTer14	frameshift	Exon 6 of 23	ENSP00000418525.1	P08473

Frequencies

GnomAD3 genomes

AF:

0.000408

AC:

AN:

151872

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000725

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00257

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:

0.000294

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000260

AC:

AN:

250084

AF XY:

0.000214

show subpopulations

Gnomad AFR exome

AF:

0.000127

Gnomad AMR exome

AF:

0.000726

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000462

Gnomad NFE exome

AF:

0.000327

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000318

AC:

464

AN:

1460970

Hom.:

Cov.:

AF XY:

0.000307

AC XY:

223

AN XY:

726690

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33458

American (AMR)

AF:

0.000515

AC:

AN:

44642

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26114

East Asian (EAS)

AF:

0.00

AC:

AN:

39618

South Asian (SAS)

AF:

0.00

AC:

AN:

85990

European-Finnish (FIN)

AF:

0.0000562

AC:

AN:

53406

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5762

European-Non Finnish (NFE)

AF:

0.000384

AC:

427

AN:

1111626

Other (OTH)

AF:

0.000182

AC:

AN:

60354

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.492

Heterozygous variant carriers

104

130

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000408

AC:

AN:

151872

Hom.:

Cov.:

AF XY:

0.000485

AC XY:

AN XY:

74156

show subpopulations

African (AFR)

AF:

0.0000725

AC:

AN:

41374

American (AMR)

AF:

0.00257

AC:

AN:

15192

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5176

South Asian (SAS)

AF:

0.00

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10540

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.000294

AC:

AN:

67988

Other (OTH)

AF:

0.00

AC:

AN:

2084

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.528

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000218

Hom.:

Bravo

AF:

0.000427

EpiCase

AF:

0.000328

EpiControl

AF:

0.000119

ClinVar

ClinVar submissions

Significance:Pathogenic/Likely pathogenic

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (9)

Charcot-Marie-Tooth disease axonal type 2T (6)

Charcot-Marie-Tooth disease axonal type 2T;C4310763:Spinocerebellar ataxia 43 (1)

Charcot-Marie-Tooth disease type 2T (1)

See cases (1)

Spinocerebellar ataxia 43 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

7.2

Mutation Taster

=0/200

disease causing (ClinVar)

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over