chr11-112025603-G-A

Variant names:

• chr11-112025603-G-A
• rs371809583
• NM_001931.5:c.131G>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001931.5(DLAT):​c.131G>A​(p.Arg44His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,618 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R44L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: DLAT NM_001931.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.507
• Publications: 0 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.0648593).

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.131G>A	p.Arg44His	missense	Exon 1 of 14	NP_001922.2
	DLAT	NM_001372031.1		c.131G>A	p.Arg44His	missense	Exon 1 of 14	NP_001358960.1
	DLAT	NM_001372032.1		c.131G>A	p.Arg44His	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.131G>A	p.Arg44His	missense	Exon 1 of 14	ENSP00000280346.7	P10515
	DLAT	ENST00000915657.1		c.131G>A	p.Arg44His	missense	Exon 1 of 14	ENSP00000585716.1
	DLAT	ENST00000713569.1		c.131G>A	p.Arg44His	missense	Exon 1 of 14	ENSP00000518862.1	P10515

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461618 Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0 AN XY: 727128

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

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26126

East Asian (EAS) AF: 0.00 AC: 0 AN: 39694

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53218

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111966

Other (OTH) AF: 0.00 AC: 0 AN: 60390

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.57
CADD	Benign	15
DANN	Uncertain	1.0
DEOGEN2	Benign	0.070	T
Eigen	Benign	-0.52
Eigen_PC	Benign	-0.65
FATHMM_MKL	Benign	0.11	N
LIST_S2	Benign	0.70	T
M_CAP	Benign	0.0084	T
MetaRNN	Benign	0.065	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.4	M
PhyloP100		0.51
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	-0.31	N
REVEL	Benign	0.043
Sift	Benign	0.57	T
Sift4G	Uncertain	0.050	T
Polyphen		0.82	P
Vest4		0.21
MutPred		0.35		Loss of sheet (P = 0.0063)
MVP		0.27
MPC		0.83
ClinPred		0.34	T
GERP RS		2.1
PromoterAI		-0.061	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.030
gMVP		0.29
Mutation Taster		=97/3	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: rs371809583; hg19: chr11-111896327;