NM_001931.5:c.46G>A

Variant names:

• chr11-112025518-G-A
• rs150145390
• NM_001931.5:c.46G>A

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.46G>A​(p.Ala16Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00118 in 1,614,018 control chromosomes in the GnomAD database, including 19 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 Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0013 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0012 (19 hom.)
• Consequence: DLAT NM_001931.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.138
• Publications: 6 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: Ambry Genetics, Orphanet, Genomics England PanelApp, G2P, 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=0.0025246143).
• BP6: Variant 11-112025518-G-A is Benign according to our data. Variant chr11-112025518-G-A is described in ClinVar as Benign. ClinVar VariationId is 137085.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.00129 (197/152314) while in subpopulation EAS AF = 0.0308 (159/5158). AF 95% confidence interval is 0.0269. There are 0 homozygotes in GnomAd4. There are 118 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 19 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.46G>A	p.Ala16Thr	missense	Exon 1 of 14	NP_001922.2
	DLAT	NM_001372031.1		c.46G>A	p.Ala16Thr	missense	Exon 1 of 14	NP_001358960.1
	DLAT	NM_001372032.1		c.46G>A	p.Ala16Thr	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.46G>A	p.Ala16Thr	missense	Exon 1 of 14	ENSP00000280346.7	P10515
	DLAT	ENST00000915657.1		c.46G>A	p.Ala16Thr	missense	Exon 1 of 14	ENSP00000585716.1
	DLAT	ENST00000713569.1		c.46G>A	p.Ala16Thr	missense	Exon 1 of 14	ENSP00000518862.1	P10515

Frequencies

GnomAD3 genomes AF: 0.00129 AC: 197 AN: 152196 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00518

Gnomad EAS AF: 0.0308

Gnomad SAS AF: 0.00186

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.00144

GnomAD2 exomes AF: 0.00283 AC: 707 AN: 249812 AF XY: 0.00275

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000290

Gnomad ASJ exome AF: 0.00747

Gnomad EAS exome AF: 0.0315

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000800

Gnomad OTH exome AF: 0.000654

GnomAD4 exome AF: 0.00116 AC: 1700 AN: 1461704 Hom.: 19 Cov.: 30 AF XY: 0.00119 AC XY: 865 AN XY: 727166

African (AFR) AF: 0.00 AC: 0 AN: 33476

American (AMR) AF: 0.0000224 AC: 1 AN: 44708

Ashkenazi Jewish (ASJ) AF: 0.00766 AC: 200 AN: 26116

East Asian (EAS) AF: 0.0314 AC: 1245 AN: 39696

South Asian (SAS) AF: 0.00130 AC: 112 AN: 86254

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53338

Middle Eastern (MID) AF: 0.000347 AC: 2 AN: 5764

European-Non Finnish (NFE) AF: 0.0000450 AC: 50 AN: 1111968

Other (OTH) AF: 0.00147 AC: 89 AN: 60384

GnomAD4 genome AF: 0.00129 AC: 197 AN: 152314 Hom.: 0 Cov.: 33 AF XY: 0.00158 AC XY: 118 AN XY: 74478

African (AFR) AF: 0.00 AC: 0 AN: 41574

American (AMR) AF: 0.000196 AC: 3 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.00518 AC: 18 AN: 3472

East Asian (EAS) AF: 0.0308 AC: 159 AN: 5158

South Asian (SAS) AF: 0.00186 AC: 9 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000735 AC: 5 AN: 68032

Other (OTH) AF: 0.00142 AC: 3 AN: 2112

Alfa AF: 0.00170 Hom.: 10

Bravo AF: 0.00168

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000465 AC: 4

ExAC AF: 0.00258 AC: 313

Asia WGS AF: 0.00924 AC: 32 AN: 3478

EpiCase AF: 0.000273

EpiControl AF: 0.000237

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	not specified (1)
-	-	1	Pyruvate dehydrogenase E2 deficiency (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.089
BayesDel_addAF	Benign	-0.58	T
BayesDel_noAF	Benign	-0.58
CADD	Benign	13
DANN	Benign	0.95
DEOGEN2	Benign	0.088	T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.078	N
LIST_S2	Benign	0.58	T
MetaRNN	Benign	0.0025	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	0.90	L
PhyloP100		0.14
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-0.36	N
REVEL	Benign	0.010
Sift	Benign	0.29	T
Sift4G	Benign	0.41	T
Polyphen		0.0	B
Vest4		0.18
MVP		0.13
MPC		0.27
ClinPred		0.011	T
GERP RS		-1.4
PromoterAI		-0.0016	Neutral
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.7
Varity_R		0.038
gMVP		0.39
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs150145390; hg19: chr11-111896242; COSMIC: COSV54769573; COSMIC: COSV54769573;