Genetic Variant ENST00000648300.1:n.-21+580G>A (chr3-128051631-G-T) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The ENST00000648300.1(MGLL):n.-1303+331C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000809 in 1,235,406 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 8.1e-7 ( 0 hom. )

Consequence

MGLL
ENST00000648300.1 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.05

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:

LOC102723759 (HGNC:):

LOC102723759 links:

SEC61A1 (HGNC:18276): (SEC61 translocon subunit alpha 1) The protein encoded by this gene belongs to the SECY/SEC61- alpha family. It appears to play a crucial role in the insertion of secretory and membrane polypeptides into the endoplasmic reticulum. This protein found to be tightly associated with membrane-bound ribosomes, either directly or through adaptor proteins. This gene encodes an alpha subunit of the heteromeric SEC61 complex, which also contains beta and gamma subunits. [provided by RefSeq, Jul 2008]

SEC61A1 Gene-Disease associations (from GenCC):

hyperuricemic nephropathy, familial juvenile type 4
Inheritance: AD Classification: STRONG, MODERATE, LIMITED Submitted by: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics
SEC61A1 deficiency
Inheritance: AD Classification: MODERATE Submitted by: ClinGen

SEC61A1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.83).

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank
LOC102723759	XR_001740900.2 link	n.214+331C>A	intron_variant	Intron 1 of 4
LOC102723759	XR_007096072.1 link	n.215-295C>A	intron_variant	Intron 1 of 1
LOC102723759	XR_007096073.1 link	n.214+331C>A	intron_variant	Intron 1 of 3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MGLL	ENST00000648300.1 link	n.-1303+331C>A		intron_variant	Intron 1 of 12			ENSP00000497905.1
SEC61A1	ENST00000464451.5 link	c.-255G>T		upstream_gene_variant		2		ENSP00000418493.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

8.09e-7

AC:

AN:

1235406

Hom.:

Cov.:

AF XY:

0.00000168

AC XY:

AN XY:

596734

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

26852

American (AMR)

AF:

0.0000600

AC:

AN:

16680

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

17612

East Asian (EAS)

AF:

0.00

AC:

AN:

30760

South Asian (SAS)

AF:

0.00

AC:

AN:

57894

European-Finnish (FIN)

AF:

0.00

AC:

AN:

27274

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3572

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1003844

Other (OTH)

AF:

0.00

AC:

AN:

50918

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.325

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

BayesDel_noAF

Benign

-0.83

CADD

Benign

5.4

(source)

DANN

Benign

0.38

PhyloP100

1.1

PromoterAI

-0.092

Neutral

(source)

Splicing

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over