Genetic Variant MME:c.-10-312C>T (chr3-155083846-C-T) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_007289.4(MME):c.-10-312C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00354 in 327,434 control chromosomes in the GnomAD database, including 14 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0066 ( 12 hom., cov: 33)

Exomes 𝑓: 0.00088 ( 2 hom. )

Consequence

MME
NM_007289.4 intron

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 0.352

Publications

0 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: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.66).

BP6

Variant 3-155083846-C-T is Benign according to our data. Variant chr3-155083846-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 1203738.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00661 (1006/152244) while in subpopulation AFR AF = 0.0228 (949/41554). AF 95% confidence interval is 0.0216. There are 12 homozygotes in GnomAd4. There are 483 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 12 SD,AD,AR gene

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	Effect	Exon Rank	Protein	UniProt
MME	NM_007289.4	MANE Select	c.-10-312C>T	intron	N/A	NP_009220.2	P08473
MME	NM_000902.5		c.-10-312C>T	intron	N/A	NP_000893.2	P08473
MME	NM_001354642.2		c.-10-312C>T	intron	N/A	NP_001341571.1	P08473

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
MME	ENST00000360490.7	TSL:1 MANE Select	c.-10-312C>T	intron	N/A	ENSP00000353679.2	P08473
MME	ENST00000615825.2	TSL:1	c.-10-312C>T	intron	N/A	ENSP00000478173.2	A0A7I2U302
MME	ENST00000460393.6	TSL:1	c.-10-312C>T	intron	N/A	ENSP00000418525.1	P08473

Frequencies

GnomAD3 genomes

AF:

0.00661

AC:

1005

AN:

152126

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0228

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00282

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000415

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000588

Gnomad OTH

AF:

0.00478

GnomAD4 exome

AF:

0.000879

AC:

154

AN:

175190

Hom.:

Cov.:

AF XY:

0.000752

AC XY:

AN XY:

95710

show subpopulations

African (AFR)

AF:

0.0256

AC:

126

AN:

4914

American (AMR)

AF:

0.00156

AC:

AN:

7044

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

4420

East Asian (EAS)

AF:

0.00

AC:

AN:

7794

South Asian (SAS)

AF:

0.0000632

AC:

AN:

31622

European-Finnish (FIN)

AF:

0.00

AC:

AN:

7900

Middle Eastern (MID)

AF:

0.00

AC:

AN:

630

European-Non Finnish (NFE)

AF:

0.0000588

AC:

AN:

102028

Other (OTH)

AF:

0.00102

AC:

AN:

8838

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.526

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

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

GnomAD4 genome

AF:

0.00661

AC:

1006

AN:

152244

Hom.:

Cov.:

AF XY:

0.00649

AC XY:

483

AN XY:

74432

show subpopulations

African (AFR)

AF:

0.0228

AC:

949

AN:

41554

American (AMR)

AF:

0.00281

AC:

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5180

South Asian (SAS)

AF:

0.00

AC:

AN:

4816

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10598

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000588

AC:

AN:

68018

Other (OTH)

AF:

0.00473

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

Heterozygous variant carriers

146

195

244

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

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

Alfa

AF:

0.00499

Hom.:

Bravo

AF:

0.00776

Asia WGS

AF:

0.00260

AC:

AN:

3472

ClinVar

ClinVar submissions

Significance:Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.66

CADD

Benign

(source)

DANN

Benign

0.71

PhyloP100

0.35

PromoterAI

0.0052

Neutral

(source)

Mutation Taster

=100/0

polymorphism

(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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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