11-112025527-G-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

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. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0069 (5 hom., cov: 33)
  • Exomes 𝑓: 0.0084 (65 hom.)
• Consequence: DLAT NM_001931.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -0.203

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]

ACMG classification

Verdict is Benign. Variant got -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]. Clinvar id is 137086.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-112025527-G-C is described in Lovd as [Likely_benign].
• 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 male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DLAT	NM_001931.5	c.55G>C	p.Glu19Gln	missense_variant	1/14	ENST00000280346.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DLAT	ENST00000280346.11	c.55G>C	p.Glu19Gln	missense_variant	1/14	1	NM_001931.5	P3

Frequencies

GnomAD3 genomes AF: 0.00686 AC: 1045 AN: 152246 Hom.: 5 Cov.: 33

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

GnomAD3 exomes AF: 0.00735 AC: 1835 AN: 249764 Hom.: 13 AF XY: 0.00741 AC XY: 1003 AN XY: 135294

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 SAS exome AF: 0.00297

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.: 65 Cov.: 30 AF XY: 0.00831 AC XY: 6042 AN XY: 727170

Gnomad4 AFR exome AF: 0.00117

Gnomad4 AMR exome AF: 0.00946

Gnomad4 ASJ exome AF: 0.00988

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.00299

Gnomad4 FIN exome AF: 0.00386

Gnomad4 NFE exome AF: 0.00942

Gnomad4 OTH exome AF: 0.00853

GnomAD4 genome AF: 0.00686 AC: 1045 AN: 152364 Hom.: 5 Cov.: 33 AF XY: 0.00651 AC XY: 485 AN XY: 74506

Gnomad4 AFR AF: 0.00173

Gnomad4 AMR AF: 0.0113

Gnomad4 ASJ AF: 0.0130

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00372

Gnomad4 FIN AF: 0.00433

Gnomad4 NFE AF: 0.00960

Gnomad4 OTH AF: 0.0104

Alfa AF: 0.00976 Hom.: 6

Bravo AF: 0.00778

TwinsUK AF: 0.0113 AC: 42

ALSPAC AF: 0.00830 AC: 32

ESP6500AA AF: 0.00159 AC: 7

ESP6500EA AF: 0.0114 AC: 98

ExAC AF: 0.00717 AC: 870

Asia WGS AF: 0.00173 AC: 6 AN: 3478

EpiCase AF: 0.0124

EpiControl AF: 0.0111

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Likely benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Feb 22, 2016	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2024	DLAT: BP4, BS1, BS2 -

Pyruvate dehydrogenase E2 deficiency Benign:3

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 30, 2021	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 14, 2023	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 05, 2012

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

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 17, 2019

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	T
BayesDel_noAF	Benign	-0.79
Cadd	Benign	9.4
Dann	Benign	0.72
DEOGEN2	Benign	0.056	T;T
Eigen	Benign	-0.85
Eigen_PC	Benign	-0.87
FATHMM_MKL	Benign	0.12	N
LIST_S2	Benign	0.60	T;T
MetaRNN	Benign	0.0033	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N;.
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.42	T
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	T
GERP RS		1.6
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.1
Varity_R		0.057
gMVP		0.29

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

LitVar

Other links and lift over

dbSNP: rs61757217; hg19: chr11-111896251;