Genetic Variant DAGLB:p.Thr545Lys (chr7-6410316-G-T) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_139179.4(DAGLB):c.1634C>A(p.Thr545Lys) variant causes a missense change. The variant allele was found at a frequency of 0.00148 in 1,614,092 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0011 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0015 ( 3 hom. )

Consequence

DAGLB
NM_139179.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.34

Variant links:

Genes affected

DAGLB (HGNC:28923): (diacylglycerol lipase beta) Enables lipase activity. Involved in arachidonic acid metabolic process. Located in nucleoplasm and plasma membrane. [provided by Alliance of Genome Resources, Apr 2022]

DAGLB links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.026246518).

BS2

High Homozygotes in GnomAdExome4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DAGLB	NM_139179.4 link	c.1634C>A	p.Thr545Lys	missense_variant	Exon 14 of 15	ENST00000297056.11	NP_631918.3	Q8NCG7-1
DAGLB	NM_001142936.2 link	c.1247C>A	p.Thr416Lys	missense_variant	Exon 12 of 13		NP_001136408.1	Q8NCG7-4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DAGLB	ENST00000297056.11 link	c.1634C>A	p.Thr545Lys	missense_variant	Exon 14 of 15	1	NM_139179.4	ENSP00000297056.6		Q8NCG7-1

Frequencies

GnomAD3 genomes

AF:

0.00105

AC:

160

AN:

152156

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000435

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000196

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000942

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00201

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.000920

AC:

231

AN:

250978

Hom.:

AF XY:

0.000914

AC XY:

124

AN XY:

135682

show subpopulations

Gnomad AFR exome

AF:

0.000431

Gnomad AMR exome

AF:

0.000116

Gnomad ASJ exome

AF:

0.000695

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000924

Gnomad NFE exome

AF:

0.00183

Gnomad OTH exome

AF:

0.000653

GnomAD4 exome

AF:

0.00153

AC:

2232

AN:

1461818

Hom.:

Cov.:

AF XY:

0.00147

AC XY:

1067

AN XY:

727200

show subpopulations

Gnomad4 AFR exome

AF:

0.000209

Gnomad4 AMR exome

AF:

0.000157

Gnomad4 ASJ exome

AF:

0.000995

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.000300

Gnomad4 NFE exome

AF:

0.00187

Gnomad4 OTH exome

AF:

0.00157

GnomAD4 genome

AF:

0.00105

AC:

160

AN:

152274

Hom.:

Cov.:

AF XY:

0.000873

AC XY:

AN XY:

74462

show subpopulations

Gnomad4 AFR

AF:

0.000433

Gnomad4 AMR

AF:

0.000196

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.0000942

Gnomad4 NFE

AF:

0.00201

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.00150

Hom.:

Bravo

AF:

0.000941

TwinsUK

AF:

0.00135

AC:

ALSPAC

AF:

0.000778

AC:

ESP6500AA

AF:

0.000681

AC:

ESP6500EA

AF:

0.00256

AC:

ExAC

AF:

0.000906

AC:

110

EpiCase

AF:

0.00185

EpiControl

AF:

0.00166

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Mar 02, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1634C>A (p.T545K) alteration is located in exon 14 (coding exon 14) of the DAGLB gene. This alteration results from a C to A substitution at nucleotide position 1634, causing the threonine (T) at amino acid position 545 to be replaced by a lysine (K). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.16

BayesDel_addAF

Benign

-0.36

BayesDel_noAF

Benign

-0.30

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.063

T;.;T

Eigen

Benign

0.11

Eigen_PC

Benign

-0.012

FATHMM_MKL

Uncertain

0.90

LIST_S2

Uncertain

0.90

D;D;D

M_CAP

Benign

0.050

MetaRNN

Benign

0.026

T;T;T

MetaSVM

Benign

-0.66

MutationAssessor

Uncertain

2.9

M;.;.

PrimateAI

Benign

0.38

PROVEAN

Benign

-1.6

N;N;N

REVEL

Benign

0.26

Sift

Benign

0.35

T;T;T

Sift4G

Uncertain

0.0070

D;D;D

Polyphen

1.0

D;.;.

Vest4

0.68

MVP

0.50

MPC

0.33

ClinPred

0.068

GERP RS

4.1

Varity_R

0.17

gMVP

0.74

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over