11-112025518-G-A

Position:

chr11-112025518-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The ENST00000280346.11(DLAT):c.46G>A(p.Ala16Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00118 in 1,614,018 control chromosomes in the GnomAD database, including 19 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0013 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0012 ( 19 hom. )

Consequence

DLAT
ENST00000280346.11 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 0.138

Variant links:

Genes affected

DLAT (HGNC:2896): (dihydrolipoamide S-acetyltransferase) This gene encodes component E2 of the multi-enzyme pyruvate dehydrogenase complex (PDC). PDC resides in the inner mitochondrial membrane and catalyzes the conversion of pyruvate to acetyl coenzyme A. The protein product of this gene, dihydrolipoamide acetyltransferase, accepts acetyl groups formed by the oxidative decarboxylation of pyruvate and transfers them to coenzyme A. Dihydrolipoamide acetyltransferase is the antigen for antimitochondrial antibodies. These autoantibodies are present in nearly 95% of patients with the autoimmune liver disease primary biliary cirrhosis (PBC). In PBC, activated T lymphocytes attack and destroy epithelial cells in the bile duct where this protein is abnormally distributed and overexpressed. PBC enventually leads to cirrhosis and liver failure. Mutations in this gene are also a cause of pyruvate dehydrogenase E2 deficiency which causes primary lactic acidosis in infancy and early childhood.[provided by RefSeq, Oct 2009]

DLAT links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0025246143).

BP6

Variant 11-112025518-G-A is Benign according to our data. Variant chr11-112025518-G-A is described in ClinVar as [Benign]. Clinvar id is 137085.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.00129 (197/152314) while in subpopulation EAS AF= 0.0308 (159/5158). AF 95% confidence interval is 0.0269. There are 0 homozygotes in gnomad4. There are 118 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAdExome4 at 19 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DLAT	NM_001931.5 linkuse as main transcript	c.46G>A	p.Ala16Thr	missense_variant	1/14	ENST00000280346.11	NP_001922.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DLAT	ENST00000280346.11 linkuse as main transcript	c.46G>A	p.Ala16Thr	missense_variant	1/14	1	NM_001931.5	ENSP00000280346	P3

Frequencies

GnomAD3 genomes

AF:

0.00129

AC:

197

AN:

152196

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000196

Gnomad ASJ

AF:

0.00518

Gnomad EAS

AF:

0.0308

Gnomad SAS

AF:

0.00186

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000735

Gnomad OTH

AF:

0.00144

GnomAD3 exomes

AF:

0.00283

AC:

707

AN:

249812

Hom.:

AF XY:

0.00275

AC XY:

372

AN XY:

135326

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000290

Gnomad ASJ exome

AF:

0.00747

Gnomad EAS exome

AF:

0.0315

Gnomad SAS exome

AF:

0.00131

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000800

Gnomad OTH exome

AF:

0.000654

GnomAD4 exome

AF:

0.00116

AC:

1700

AN:

1461704

Hom.:

Cov.:

AF XY:

0.00119

AC XY:

865

AN XY:

727166

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00766

Gnomad4 EAS exome

AF:

0.0314

Gnomad4 SAS exome

AF:

0.00130

Gnomad4 FIN exome

AF:

0.0000187

Gnomad4 NFE exome

AF:

0.0000450

Gnomad4 OTH exome

AF:

0.00147

GnomAD4 genome

AF:

0.00129

AC:

197

AN:

152314

Hom.:

Cov.:

AF XY:

0.00158

AC XY:

118

AN XY:

74478

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000196

Gnomad4 ASJ

AF:

0.00518

Gnomad4 EAS

AF:

0.0308

Gnomad4 SAS

AF:

0.00186

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000735

Gnomad4 OTH

AF:

0.00142

Alfa

AF:

0.00183

Hom.:

Bravo

AF:

0.00168

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000465

AC:

ExAC

AF:

0.00258

AC:

313

Asia WGS

AF:

0.00924

AC:

AN:

3478

EpiCase

AF:

0.000273

EpiControl

AF:

0.000237

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Dec 31, 2013

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Pyruvate dehydrogenase E2 deficiency

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 07, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.089

BayesDel_addAF

Benign

-0.58

BayesDel_noAF

Benign

-0.58

CADD

Benign

DANN

Benign

0.95

DEOGEN2

Benign

0.088

T;T

Eigen

Benign

-1.4

Eigen_PC

Benign

-1.4

FATHMM_MKL

Benign

0.078

LIST_S2

Benign

0.58

T;T

MetaRNN

Benign

0.0025

T;T

MetaSVM

Benign

-0.96

MutationAssessor

Benign

0.90

L;.

MutationTaster

Benign

1.0

N;N

PrimateAI

Benign

0.43

PROVEAN

Benign

-0.36

N;N

REVEL

Benign

0.010

Sift

Benign

0.29

T;D

Sift4G

Benign

0.41

T;T

Polyphen

0.0

B;B

Vest4

0.18

MVP

0.13

MPC

0.27

ClinPred

0.011

GERP RS

-1.4

RBP_binding_hub_radar

0.92

RBP_regulation_power_radar

2.7

Varity_R

0.038

gMVP

0.39

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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