11-112025600-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001931.5(DLAT):c.128C>T(p.Ala43Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.363 in 1,613,720 control chromosomes in the GnomAD database, including 108,574 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

Frequency

Genomes: 𝑓 0.33 ( 9012 hom., cov: 32)

Exomes 𝑓: 0.37 ( 99562 hom. )

Consequence

DLAT
NM_001931.5 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: -0.446

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=3.2565556E-5).

BP6

Variant 11-112025600-C-T is Benign according to our data. Variant chr11-112025600-C-T is described in ClinVar as [Benign]. Clinvar id is 128897.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-112025600-C-T is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.564 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DLAT	NM_001931.5 linkuse as main transcript	c.128C>T	p.Ala43Val	missense_variant	1/14	ENST00000280346.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DLAT	ENST00000280346.11 linkuse as main transcript	c.128C>T	p.Ala43Val	missense_variant	1/14	1	NM_001931.5	P3

Frequencies

GnomAD3 genomes

AF:

0.334

AC:

50799

AN:

152024

Hom.:

9011

Cov.:

show subpopulations

Gnomad AFR

AF:

0.226

Gnomad AMI

AF:

0.552

Gnomad AMR

AF:

0.339

Gnomad ASJ

AF:

0.282

Gnomad EAS

AF:

0.581

Gnomad SAS

AF:

0.397

Gnomad FIN

AF:

0.434

Gnomad MID

AF:

0.373

Gnomad NFE

AF:

0.360

Gnomad OTH

AF:

0.314

GnomAD3 exomes

AF:

0.380

AC:

94757

AN:

249216

Hom.:

18833

AF XY:

0.380

AC XY:

51395

AN XY:

135082

show subpopulations

Gnomad AFR exome

AF:

0.223

Gnomad AMR exome

AF:

0.409

Gnomad ASJ exome

AF:

0.291

Gnomad EAS exome

AF:

0.593

Gnomad SAS exome

AF:

0.401

Gnomad FIN exome

AF:

0.434

Gnomad NFE exome

AF:

0.353

Gnomad OTH exome

AF:

0.354

GnomAD4 exome

AF:

0.366

AC:

534478

AN:

1461578

Hom.:

99562

Cov.:

AF XY:

0.367

AC XY:

267049

AN XY:

727108

show subpopulations

Gnomad4 AFR exome

AF:

0.219

Gnomad4 AMR exome

AF:

0.401

Gnomad4 ASJ exome

AF:

0.286

Gnomad4 EAS exome

AF:

0.567

Gnomad4 SAS exome

AF:

0.402

Gnomad4 FIN exome

AF:

0.426

Gnomad4 NFE exome

AF:

0.358

Gnomad4 OTH exome

AF:

0.359

GnomAD4 genome

AF:

0.334

AC:

50824

AN:

152142

Hom.:

9012

Cov.:

AF XY:

0.342

AC XY:

25423

AN XY:

74356

show subpopulations

Gnomad4 AFR

AF:

0.226

Gnomad4 AMR

AF:

0.339

Gnomad4 ASJ

AF:

0.282

Gnomad4 EAS

AF:

0.582

Gnomad4 SAS

AF:

0.397

Gnomad4 FIN

AF:

0.434

Gnomad4 NFE

AF:

0.360

Gnomad4 OTH

AF:

0.315

Alfa

AF:

0.351

Hom.:

17203

Bravo

AF:

0.325

TwinsUK

AF:

0.355

AC:

1315

ALSPAC

AF:

0.366

AC:

1410

ESP6500AA

AF:

0.223

AC:

983

ESP6500EA

AF:

0.346

AC:

2969

ExAC

AF:

0.373

AC:

45291

Asia WGS

AF:

0.433

AC:

1507

AN:

3478

EpiCase

AF:

0.347

EpiControl

AF:

0.349

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Feb 15, 2016	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -

Pyruvate dehydrogenase E2 deficiency

Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 30, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

not specified

Benign:1

Likely benign, no assertion criteria provided

clinical testing

Genetic Services Laboratory, University of Chicago

Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.073

BayesDel_addAF

Benign

-0.77

BayesDel_noAF

Benign

-0.73

Cadd

Benign

9.2

Dann

Uncertain

0.97

DEOGEN2

Benign

0.033

T;T;T

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.4

FATHMM_MKL

Benign

0.050

LIST_S2

Benign

0.51

T;T;T

MetaRNN

Benign

0.000033

T;T;T

MetaSVM

Benign

-0.97

MutationAssessor

Benign

0.92

L;.;.

MutationTaster

Benign

1.0

P;P;P

PrimateAI

Benign

0.41

PROVEAN

Benign

0.13

N;N;N

REVEL

Benign

0.0090

Sift

Benign

0.49

T;T;D

Sift4G

Benign

0.12

T;T;D

Polyphen

0.0010

B;B;.

Vest4

0.16

MPC

0.28

ClinPred

0.0050

GERP RS

-2.8

Varity_R

0.024

gMVP

0.20

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