3-127695133-C-T

Variant names:

• chr3-127695133-C-T
• rs138122374
• NM_007283.7:c.658G>A

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BP6 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 (no stars).

• 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 no assertion criteria provided 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

Our verdict: Benign. The variant received -9 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 no_assertion_criteria_provided, 0 stars.
• BS2: High Homozygotes in GnomAdExome4 at 13 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MGLL	NM_007283.7	c.658G>A	p.Gly220Ser	missense_variant	Exon 7 of 8	ENST00000265052.10	NP_009214.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MGLL	ENST00000265052.10	c.658G>A	p.Gly220Ser	missense_variant	Exon 7 of 8	1	NM_007283.7	ENSP00000265052.5

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

GnomAD2 exomes AF: 0.00311 AC: 777 AN: 249442 AF XY: 0.00272

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 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 AC: 2 AN: 33480

Gnomad4 AMR exome AF: 0.0110 AC: 492 AN: 44724

Gnomad4 ASJ exome AF: 0.000727 AC: 19 AN: 26136

Gnomad4 EAS exome AF: 0.0106 AC: 422 AN: 39700

Gnomad4 SAS exome AF: 0.00153 AC: 132 AN: 86256

Gnomad4 FIN exome AF: 0.00326 AC: 174 AN: 53380

Gnomad4 NFE exome AF: 0.000117 AC: 130 AN: 1112008

Gnomad4 Remaining exome AF: 0.00121 AC: 73 AN: 60396

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 AC: 0.0000481301 AN: 0.0000481301

Gnomad4 AMR AF: 0.00621 AC: 0.00620672 AN: 0.00620672

Gnomad4 ASJ AF: 0.00144 AC: 0.00144175 AN: 0.00144175

Gnomad4 EAS AF: 0.0125 AC: 0.0125386 AN: 0.0125386

Gnomad4 SAS AF: 0.00270 AC: 0.00269822 AN: 0.00269822

Gnomad4 FIN AF: 0.00301 AC: 0.00301489 AN: 0.00301489

Gnomad4 NFE AF: 0.000147 AC: 0.000146994 AN: 0.000146994

Gnomad4 OTH AF: 0.000948 AC: 0.000947867 AN: 0.000947867

Alfa AF: 0.00102 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: no assertion criteria provided

Submissions by phenotype

MGLL-related disorder Benign:1

Mar 29, 2019

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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
DEOGEN2	Benign	0.071	.;.;T;T;.;.;T
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
MutationAssessor	Uncertain	2.5	.;.;M;M;.;.;.
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
Mutation Taster		=89/11	polymorphism

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;