NM_001931.5:c.128C>T

Variant names:

• chr11-112025600-C-T
• rs2303436
• NM_001931.5:c.128C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.446
• Publications: 48 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=3.2565556E-5).
• BP6: Variant 11-112025600-C-T is Benign according to our data. Variant chr11-112025600-C-T is described in ClinVar as Benign. ClinVar VariationId 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.

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.128C>T	p.Ala43Val	missense	Exon 1 of 14	NP_001922.2
	DLAT	NM_001372031.1		c.128C>T	p.Ala43Val	missense	Exon 1 of 14	NP_001358960.1
	DLAT	NM_001372032.1		c.128C>T	p.Ala43Val	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.128C>T	p.Ala43Val	missense	Exon 1 of 14	ENSP00000280346.7	P10515
	DLAT	ENST00000915657.1		c.128C>T	p.Ala43Val	missense	Exon 1 of 14	ENSP00000585716.1
	DLAT	ENST00000713569.1		c.128C>T	p.Ala43Val	missense	Exon 1 of 14	ENSP00000518862.1	P10515

Frequencies

GnomAD3 genomes AF: 0.334 AC: 50799 AN: 152024 Hom.: 9011 Cov.: 32

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

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.: 80 AF XY: 0.367 AC XY: 267049 AN XY: 727108

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

GnomAD4 genome AF: 0.334 AC: 50824 AN: 152142 Hom.: 9012 Cov.: 32 AF XY: 0.342 AC XY: 25423 AN XY: 74356

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

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

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	2	Pyruvate dehydrogenase E2 deficiency (2)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.073
BayesDel_addAF	Benign	-0.77	T
BayesDel_noAF	Benign	-0.73
CADD	Benign	9.2
DANN	Uncertain	0.97
DEOGEN2	Benign	0.033	T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.050	N
LIST_S2	Benign	0.51	T
MetaRNN	Benign	0.000033	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	0.92	L
PhyloP100		-0.45
PrimateAI	Benign	0.41	T
PROVEAN	Benign	0.13	N
REVEL	Benign	0.0090
Sift	Benign	0.49	T
Sift4G	Benign	0.12	T
Polyphen		0.0010	B
Vest4		0.16
MPC		0.28
ClinPred		0.0050	T
GERP RS		-2.8
PromoterAI		0.0016	Neutral
Varity_R		0.024
gMVP		0.20
Mutation Taster		=99/1	polymorphism (auto)

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: rs2303436; hg19: chr11-111896324; COSMIC: COSV54769437; COSMIC: COSV54769437;