NM_001931.5:c.55G>C

Variant names:

• chr11-112025527-G-C
• rs61757217
• NM_001931.5:c.55G>C

Variant summary

Our verdict is Benign. The variant received -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. 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
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -0.203
• Publications: 14 publications found

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: G2P, Orphanet, Genomics England PanelApp, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• Leigh syndrome

  Inheritance: AR Classification: MODERATE Submitted by: ClinGen

ACMG classification

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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001931.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DLAT	NM_001931.5	MANE Select	c.55G>C	p.Glu19Gln	missense	Exon 1 of 14	NP_001922.2
	DLAT	NM_001372031.1		c.55G>C	p.Glu19Gln	missense	Exon 1 of 14	NP_001358960.1
	DLAT	NM_001372032.1		c.55G>C	p.Glu19Gln	missense	Exon 1 of 14	NP_001358961.1	A0A7P0TBE2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DLAT	ENST00000280346.11	TSL:1 MANE Select	c.55G>C	p.Glu19Gln	missense	Exon 1 of 14	ENSP00000280346.7	P10515
	DLAT	ENST00000915657.1		c.55G>C	p.Glu19Gln	missense	Exon 1 of 14	ENSP00000585716.1
	DLAT	ENST00000713569.1		c.55G>C	p.Glu19Gln	missense	Exon 1 of 14	ENSP00000518862.1	P10515

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

GnomAD2 exomes AF: 0.00735 AC: 1835 AN: 249764 AF XY: 0.00741

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

African (AFR) AF: 0.00117 AC: 39 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: 2 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

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

African (AFR) AF: 0.00173 AC: 72 AN: 41582

American (AMR) AF: 0.0113 AC: 173 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.0130 AC: 45 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5182

South Asian (SAS) AF: 0.00372 AC: 18 AN: 4834

European-Finnish (FIN) AF: 0.00433 AC: 46 AN: 10628

Middle Eastern (MID) AF: 0.0510 AC: 15 AN: 294

European-Non Finnish (NFE) AF: 0.00960 AC: 653 AN: 68036

Other (OTH) AF: 0.0104 AC: 22 AN: 2114

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

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not provided (5)
-	-	3	Pyruvate dehydrogenase E2 deficiency (3)
-	-	1	DLAT-related disorder (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

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
Eigen	Benign	-0.85
Eigen_PC	Benign	-0.87
FATHMM_MKL	Benign	0.12	N
LIST_S2	Benign	0.60	T
MetaRNN	Benign	0.0033	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N
PhyloP100		-0.20
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-0.10	N
REVEL	Benign	0.022
Sift	Benign	0.42	T
Sift4G	Benign	0.61	T
Polyphen		0.0	B
Vest4		0.064
MVP		0.16
MPC		0.28
ClinPred		0.0064	T
GERP RS		1.6
PromoterAI		0.052	Neutral
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.1
Varity_R		0.057
gMVP		0.29
Mutation Taster		=99/1	polymorphism

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

Other links and lift over

dbSNP: rs61757217; hg19: chr11-111896251;