NM_001931.5:c.55G>C

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001931.5(DLAT):c.55G>C(p.Glu19Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00827 in 1,614,048 control chromosomes in the GnomAD database, including 70 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0069 ( 5 hom., cov: 33)

Exomes 𝑓: 0.0084 ( 65 hom. )

Consequence

DLAT
NM_001931.5 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: -0.203

Publications

14 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=0.0032835007).

BP6

Variant 11-112025527-G-C is Benign according to our data. Variant chr11-112025527-G-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 137086.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00686 (1045/152364) while in subpopulation AMR AF = 0.0113 (173/15310). AF 95% confidence interval is 0.00992. There are 5 homozygotes in GnomAd4. There are 485 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DLAT	NM_001931.5 link	c.55G>C	p.Glu19Gln	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.55G>C	p.Glu19Gln	missense_variant	Exon 1 of 14	1	NM_001931.5	ENSP00000280346.7		P10515

Frequencies

GnomAD3 genomes

AF:

0.00686

AC:

1045

AN:

152246

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00174

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0113

Gnomad ASJ

AF:

0.0130

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00372

Gnomad FIN

AF:

0.00433

Gnomad MID

AF:

0.0475

Gnomad NFE

AF:

0.00960

Gnomad OTH

AF:

0.0105

GnomAD2 exomes

AF:

0.00735

AC:

1835

AN:

249764

AF XY:

0.00741

show subpopulations

Gnomad AFR exome

AF:

0.00168

Gnomad AMR exome

AF:

0.00866

Gnomad ASJ exome

AF:

0.00966

Gnomad EAS exome

AF:

0.0000545

Gnomad FIN exome

AF:

0.00399

Gnomad NFE exome

AF:

0.0104

Gnomad OTH exome

AF:

0.0106

GnomAD4 exome

AF:

0.00842

AC:

12311

AN:

1461684

Hom.:

Cov.:

AF XY:

0.00831

AC XY:

6042

AN XY:

727170

show subpopulations

African (AFR)

AF:

0.00117

AC:

AN:

33476

American (AMR)

AF:

0.00946

AC:

423

AN:

44708

Ashkenazi Jewish (ASJ)

AF:

0.00988

AC:

258

AN:

26116

East Asian (EAS)

AF:

0.0000504

AC:

AN:

39694

South Asian (SAS)

AF:

0.00299

AC:

258

AN:

86250

European-Finnish (FIN)

AF:

0.00386

AC:

206

AN:

53330

Middle Eastern (MID)

AF:

0.0236

AC:

136

AN:

5758

European-Non Finnish (NFE)

AF:

0.00942

AC:

10474

AN:

1111968

Other (OTH)

AF:

0.00853

AC:

515

AN:

60384

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.493

Heterozygous variant carriers

810

1620

2431

3241

4051

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

396

792

1188

1584

1980

<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:

0.00686

AC:

1045

AN:

152364

Hom.:

Cov.:

AF XY:

0.00651

AC XY:

485

AN XY:

74506

show subpopulations

African (AFR)

AF:

0.00173

AC:

AN:

41582

American (AMR)

AF:

0.0113

AC:

173

AN:

15310

Ashkenazi Jewish (ASJ)

AF:

0.0130

AC:

AN:

3472

East Asian (EAS)

AF:

0.000193

AC:

AN:

5182

South Asian (SAS)

AF:

0.00372

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.00433

AC:

AN:

10628

Middle Eastern (MID)

AF:

0.0510

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00960

AC:

653

AN:

68036

Other (OTH)

AF:

0.0104

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

107

161

214

268

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.00976

Hom.:

Bravo

AF:

0.00778

TwinsUK

AF:

0.0113

AC:

ALSPAC

AF:

0.00830

AC:

ESP6500AA

AF:

0.00159

AC:

ESP6500EA

AF:

0.0114

AC:

ExAC

AF:

0.00717

AC:

870

Asia WGS

AF:

0.00173

AC:

AN:

3478

EpiCase

AF:

0.0124

EpiControl

AF:

0.0111

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:5

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

May 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

DLAT: BP4, BS2 -

Feb 22, 2016

Mayo Clinic Laboratories, Mayo Clinic

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Pyruvate dehydrogenase E2 deficiency

Benign:3

Oct 14, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 31, 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

Jun 05, 2012

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

DLAT-related disorder

Benign:1

Dec 17, 2019

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.083

BayesDel_addAF

Benign

-0.72

BayesDel_noAF

Benign

-0.79

CADD

Benign

9.4

(source)

DANN

Benign

0.72

DEOGEN2

Benign

0.056

T;T

Eigen

Benign

-0.85

Eigen_PC

Benign

-0.87

FATHMM_MKL

Benign

0.12

LIST_S2

Benign

0.60

T;T

MetaRNN

Benign

0.0033

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.0

N;.

PhyloP100

-0.20

PrimateAI

Benign

0.42

PROVEAN

Benign

-0.10

N;N

REVEL

Benign

0.022

Sift

Benign

0.42

T;T

Sift4G

Benign

0.61

T;T

Polyphen

0.0

B;P

Vest4

0.064

MVP

0.16

MPC

0.28

ClinPred

0.0064

GERP RS

1.6

PromoterAI

0.052

Neutral

(source)

RBP_binding_hub_radar

0.92

RBP_regulation_power_radar

2.1

Varity_R

0.057

gMVP

0.29

Mutation Taster

=99/1

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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