3-127692221-C-T

Variant names:

• chr3-127692221-C-T
• rs138910107
• NM_007283.7:c.919G>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.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. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (no stars).

• 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 no assertion criteria provided B:1
• Conservation: PhyloP100: 0.248
• Publications: 9 publications found

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=0.0033406615).
• 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 no_assertion_criteria_provided, 0 stars.
• BS2: High Homozygotes in GnomAd4 at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MGLL	NM_007283.7	c.919G>A	p.Ala307Thr	missense_variant	Exon 8 of 8	ENST00000265052.10	NP_009214.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MGLL	ENST00000265052.10	c.919G>A	p.Ala307Thr	missense_variant	Exon 8 of 8	1	NM_007283.7	ENSP00000265052.5

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

GnomAD2 exomes AF: 0.00352 AC: 879 AN: 249570 AF XY: 0.00338

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 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

African (AFR) AF: 0.000896 AC: 30 AN: 33480

American (AMR) AF: 0.000581 AC: 26 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.000417 AC: 36 AN: 86258

European-Finnish (FIN) AF: 0.0135 AC: 720 AN: 53390

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5768

European-Non Finnish (NFE) AF: 0.00549 AC: 6100 AN: 1111968

Other (OTH) AF: 0.00311 AC: 188 AN: 60394

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

African (AFR) AF: 0.000845 AC: 35 AN: 41420

American (AMR) AF: 0.00138 AC: 21 AN: 15228

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5124

South Asian (SAS) AF: 0.000831 AC: 4 AN: 4816

European-Finnish (FIN) AF: 0.0164 AC: 173 AN: 10528

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 290

European-Non Finnish (NFE) AF: 0.00431 AC: 293 AN: 67986

Other (OTH) AF: 0.00190 AC: 4 AN: 2108

Alfa AF: 0.00378 Hom.: 1

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: no assertion criteria provided

Submissions by phenotype

MGLL-related disorder Benign:1

Mar 12, 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	0.071
BayesDel_addAF	Benign	-0.48	T
BayesDel_noAF	Benign	-0.45
CADD	Benign	4.1
DANN	Benign	0.86
DEOGEN2	Benign	0.084	.;.;T;T;T;.;T
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
MutationAssessor	Benign	0.69	.;.;N;N;.;.;.
PhyloP100		0.25
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
Mutation Taster		=99/1	polymorphism

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

Other links and lift over

dbSNP: rs138910107; hg19: chr3-127411064; COSMIC: COSV106090977;