Genetic Variant NM_007283.7:c.437C>A (chr3-127721126-G-T) – ACMG Classification: Likely_pathogenic (6 pts)

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2PP3_Strong

The NM_007283.7(MGLL):c.437C>A(p.Pro146Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,878 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P146L) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

MGLL
NM_007283.7 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 7.61

Publications

0 publications found

Variant links:

Genes affected

MGLL (HGNC:17038): (monoglyceride lipase) This gene encodes a serine hydrolase of the AB hydrolase superfamily that catalyzes the conversion of monoacylglycerides to free fatty acids and glycerol. The encoded protein plays a critical role in several physiological processes including pain and nociperception through hydrolysis of the endocannabinoid 2-arachidonoylglycerol. Expression of this gene may play a role in cancer tumorigenesis and metastasis. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene. [provided by RefSeq, Feb 2012]

MGLL links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.943

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MGLL	NM_007283.7 link	c.437C>A	p.Pro146Gln	missense_variant	Exon 5 of 8	ENST00000265052.10	NP_009214.1	Q99685A0A0C4DFN3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MGLL	ENST00000265052.10 link	c.437C>A	p.Pro146Gln	missense_variant	Exon 5 of 8	1	NM_007283.7	ENSP00000265052.5		A0A0C4DFN3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1461878

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727244

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53404

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00000180

AC:

AN:

1112012

Other (OTH)

AF:

0.00

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.550

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.24

BayesDel_addAF

Pathogenic

0.32

BayesDel_noAF

Pathogenic

0.23

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.21

.;.;T;T;T;.;.;T;T

Eigen

Uncertain

0.59

Eigen_PC

Uncertain

0.53

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.95

D;D;D;.;D;D;D;D;D

M_CAP

Uncertain

0.22

MetaRNN

Pathogenic

0.94

D;D;D;D;D;D;D;D;D

MetaSVM

Uncertain

0.47

MutationAssessor

Uncertain

2.3

.;.;M;M;.;.;.;.;.

PhyloP100

7.6

PrimateAI

Uncertain

0.51

PROVEAN

Pathogenic

-6.9

D;D;D;D;D;D;.;D;D

REVEL

Pathogenic

0.70

Sift

Uncertain

0.0020

D;D;D;D;D;D;.;D;D

Sift4G

Uncertain

0.0060

D;D;D;D;T;T;.;T;.

Polyphen

1.0

.;.;D;D;.;D;.;.;.

Vest4

0.76

MutPred

0.68

.;.;Gain of glycosylation at T131 (P = 0.0341);Gain of glycosylation at T131 (P = 0.0341);.;.;Gain of glycosylation at T131 (P = 0.0341);.;.;

MVP

0.99

MPC

1.2

ClinPred

0.99

GERP RS

5.3

PromoterAI

0.017

Neutral

(source)

Varity_R

0.77

gMVP

0.83

Mutation Taster

=14/86

disease causing

(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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NM_007283.7:c.437C>A

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over