3-127692221-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.919G>A(p.Ala307Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00473 in 1,613,696 control chromosomes in the GnomAD database, including 43 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0035 (5 hom., cov: 31)
  • Exomes 𝑓: 0.0049 (38 hom.)
• Consequence: MGLL NM_007283.7 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.248

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=0.0033406615).
• BP6: Variant 3-127692221-C-T is Benign according to our data. Variant chr3-127692221-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 3039230.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Homozygotes in GnomAd at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MGLL	NM_007283.7	c.919G>A	p.Ala307Thr	missense_variant	8/8	ENST00000265052.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MGLL	ENST00000265052.10	c.919G>A	p.Ala307Thr	missense_variant	8/8	1	NM_007283.7

Frequencies

GnomAD3 genomes AF: 0.00349 AC: 530 AN: 151762 Hom.: 5 Cov.: 31

Gnomad AFR AF: 0.000847

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00138

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000830

Gnomad FIN AF: 0.0164

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00431

Gnomad OTH AF: 0.00192

GnomAD3 exomes AF: 0.00352 AC: 879 AN: 249570 Hom.: 6 AF XY: 0.00338 AC XY: 458 AN XY: 135406

Gnomad AFR exome AF: 0.00103

Gnomad AMR exome AF: 0.000290

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000294

Gnomad FIN exome AF: 0.0142

Gnomad NFE exome AF: 0.00461

Gnomad OTH exome AF: 0.00264

GnomAD4 exome AF: 0.00486 AC: 7102 AN: 1461816 Hom.: 38 Cov.: 35 AF XY: 0.00466 AC XY: 3391 AN XY: 727214

Gnomad4 AFR exome AF: 0.000896

Gnomad4 AMR exome AF: 0.000581

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000417

Gnomad4 FIN exome AF: 0.0135

Gnomad4 NFE exome AF: 0.00549

Gnomad4 OTH exome AF: 0.00311

GnomAD4 genome AF: 0.00349 AC: 530 AN: 151880 Hom.: 5 Cov.: 31 AF XY: 0.00408 AC XY: 303 AN XY: 74194

Gnomad4 AFR AF: 0.000845

Gnomad4 AMR AF: 0.00138

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000831

Gnomad4 FIN AF: 0.0164

Gnomad4 NFE AF: 0.00431

Gnomad4 OTH AF: 0.00190

Alfa AF: 0.00412 Hom.: 0

Bravo AF: 0.00257

TwinsUK AF: 0.00647 AC: 24

ALSPAC AF: 0.00571 AC: 22

ESP6500AA AF: 0.000262 AC: 1

ESP6500EA AF: 0.00437 AC: 36

ExAC AF: 0.00320 AC: 387

EpiCase AF: 0.00371

EpiControl AF: 0.00320

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 12, 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	0.071
BayesDel_addAF	Benign	-0.48	T
BayesDel_noAF	Benign	-0.45
Cadd	Benign	4.1
Dann	Benign	0.86
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.15	N
LIST_S2	Benign	0.70	T;T;T;.;T;T;T
MetaRNN	Benign	0.0033	T;T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	N;N;N;N;N
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-0.34	N;N;N;N;N;N;N
REVEL	Benign	0.018
Sift	Benign	0.40	T;T;T;T;D;T;T
Sift4G	Benign	0.26	T;T;T;T;T;T;T
Polyphen		0.0	.;.;B;B;.;B;.
Vest4		0.050
MVP		0.048
MPC		0.43
ClinPred		0.00067	T
GERP RS		1.1
Varity_R		0.024
gMVP		0.26

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

LitVar

Other links and lift over

dbSNP: rs138910107; hg19: chr3-127411064;