11-112025600-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -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. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

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:6

Conservation

PhyloP100: -0.446

Publications

48 publications found

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 Gene-Disease associations (from GenCC):

pyruvate dehydrogenase E2 deficiency
Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: Orphanet, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P
Leigh syndrome
Inheritance: AR Classification: MODERATE Submitted by: ClinGen

DLAT links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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 CliVar 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 CliVar 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 CliVar 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 CliVar 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 CliVar 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 CliVar 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 CliVar 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 CliVar 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 CliVar 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 CliVar 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 CliVar 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 CliVar 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 CliVar 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 CliVar 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 CliVar 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 CliVar 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 CliVar 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 CliVar 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 CliVar 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 CliVar 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 CliVar 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 CliVar 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 CliVar 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 CliVar 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 CliVar 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 CliVar 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 CliVar 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 CliVar 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 CliVar 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 CliVar 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 CliVar 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 CliVar as Benign. Clinvar id is 128897.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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 rank	MANE	Protein	UniProt
DLAT	NM_001931.5 link	c.128C>T	p.Ala43Val	missense_variant	Exon 1 of 14	ENST00000280346.11	NP_001922.2	P10515Q86YI5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DLAT	ENST00000280346.11 link	c.128C>T	p.Ala43Val	missense_variant	Exon 1 of 14	1	NM_001931.5	ENSP00000280346.7		P10515

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

GnomAD2 exomes

AF:

0.380

AC:

94757

AN:

249216

AF XY:

0.380

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 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

African (AFR)

AF:

0.219

AC:

7318

AN:

33476

American (AMR)

AF:

0.401

AC:

17935

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.286

AC:

7468

AN:

26124

East Asian (EAS)

AF:

0.567

AC:

22503

AN:

39692

South Asian (SAS)

AF:

0.402

AC:

34650

AN:

86256

European-Finnish (FIN)

AF:

0.426

AC:

22649

AN:

53218

Middle Eastern (MID)

AF:

0.359

AC:

2070

AN:

5768

European-Non Finnish (NFE)

AF:

0.358

AC:

398218

AN:

1111932

Other (OTH)

AF:

0.359

AC:

21667

AN:

60390

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.484

Heterozygous variant carriers

24857

49714

74572

99429

124286

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

12778

25556

38334

51112

63890

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.334

AC:

50824

AN:

152142

Hom.:

9012

Cov.:

AF XY:

0.342

AC XY:

25423

AN XY:

74356

show subpopulations

African (AFR)

AF:

0.226

AC:

9390

AN:

41542

American (AMR)

AF:

0.339

AC:

5183

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.282

AC:

977

AN:

3470

East Asian (EAS)

AF:

0.582

AC:

3005

AN:

5166

South Asian (SAS)

AF:

0.397

AC:

1914

AN:

4816

European-Finnish (FIN)

AF:

0.434

AC:

4589

AN:

10584

Middle Eastern (MID)

AF:

0.381

AC:

112

AN:

294

European-Non Finnish (NFE)

AF:

0.360

AC:

24488

AN:

67960

Other (OTH)

AF:

0.315

AC:

667

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

1697

3394

5092

6789

8486

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

520

1040

1560

2080

2600

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.349

Hom.:

35735

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:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Mar 03, 2015

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Feb 15, 2016

Mayo Clinic Laboratories, Mayo Clinic

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Pyruvate dehydrogenase E2 deficiency

Benign:2

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jul 30, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:1

Genetic Services Laboratory, University of Chicago

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

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

(source)

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;.;.

PhyloP100

-0.45

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

PromoterAI

0.0016

Neutral

(source)

Varity_R

0.024

gMVP

0.20

Mutation Taster

=99/1

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over