3-127695133-C-T

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_007283.7(MGLL):c.658G>A(p.Gly220Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00103 in 1,614,136 control chromosomes in the GnomAD database, including 13 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0015 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00099 (13 hom.)
• Consequence: MGLL NM_007283.7 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 4.22

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]

ACMG classification

Verdict is Benign. Variant got -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0077992976).
• BP6: Variant 3-127695133-C-T is Benign according to our data. Variant chr3-127695133-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 3042845.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Homozygotes in GnomAdExome at 11 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MGLL	NM_007283.7	c.658G>A	p.Gly220Ser	missense_variant	7/8	ENST00000265052.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MGLL	ENST00000265052.10	c.658G>A	p.Gly220Ser	missense_variant	7/8	1	NM_007283.7

Frequencies

GnomAD3 genomes AF: 0.00147 AC: 223 AN: 152172 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00621

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.0125

Gnomad SAS AF: 0.00249

Gnomad FIN AF: 0.00301

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000147

Gnomad OTH AF: 0.000958

GnomAD3 exomes AF: 0.00311 AC: 777 AN: 249442 Hom.: 11 AF XY: 0.00272 AC XY: 368 AN XY: 135372

Gnomad AFR exome AF: 0.000129

Gnomad AMR exome AF: 0.0114

Gnomad ASJ exome AF: 0.000993

Gnomad EAS exome AF: 0.0124

Gnomad SAS exome AF: 0.00154

Gnomad FIN exome AF: 0.00311

Gnomad NFE exome AF: 0.000168

Gnomad OTH exome AF: 0.00231

GnomAD4 exome AF: 0.000988 AC: 1444 AN: 1461846 Hom.: 13 Cov.: 32 AF XY: 0.000939 AC XY: 683 AN XY: 727232

Gnomad4 AFR exome AF: 0.0000597

Gnomad4 AMR exome AF: 0.0110

Gnomad4 ASJ exome AF: 0.000727

Gnomad4 EAS exome AF: 0.0106

Gnomad4 SAS exome AF: 0.00153

Gnomad4 FIN exome AF: 0.00326

Gnomad4 NFE exome AF: 0.000117

Gnomad4 OTH exome AF: 0.00121

GnomAD4 genome AF: 0.00147 AC: 224 AN: 152290 Hom.: 0 Cov.: 32 AF XY: 0.00168 AC XY: 125 AN XY: 74464

Gnomad4 AFR AF: 0.0000481

Gnomad4 AMR AF: 0.00621

Gnomad4 ASJ AF: 0.00144

Gnomad4 EAS AF: 0.0125

Gnomad4 SAS AF: 0.00270

Gnomad4 FIN AF: 0.00301

Gnomad4 NFE AF: 0.000147

Gnomad4 OTH AF: 0.000948

Alfa AF: 0.000872 Hom.: 0

Bravo AF: 0.00201

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000357 AC: 3

ExAC AF: 0.00251 AC: 304

Asia WGS AF: 0.00577 AC: 20 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.000178

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

MGLL-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 29, 2019

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.32
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.17
Cadd	Benign	18
Dann	Uncertain	1.0
Eigen	Uncertain	0.32
Eigen_PC	Uncertain	0.31
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.95	D;D;D;.;D;D;D
MetaRNN	Benign	0.0078	T;T;T;T;T;T;T
MetaSVM	Uncertain	-0.22	T
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Uncertain	0.53	T
PROVEAN	Benign	-1.1	N;N;N;N;N;.;N
REVEL	Uncertain	0.36
Sift	Benign	0.42	T;T;T;T;T;.;T
Sift4G	Benign	0.17	T;T;T;T;T;.;T
Polyphen		0.86, 0.95	.;.;P;P;P;.;.
Vest4		0.50
MVP		0.86
MPC		0.60
ClinPred		0.025	T
GERP RS		5.0
Varity_R		0.49
gMVP		0.78

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs138122374; hg19: chr3-127413976; COSMIC: COSV54022868;