11-112025555-T-C

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001931.5(DLAT):c.83T>C(p.Val28Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000479 in 1,461,676 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000048 (0 hom.)
• Consequence: DLAT NM_001931.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.120

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 Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.029635131).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DLAT	NM_001931.5	c.83T>C	p.Val28Ala	missense_variant	1/14	ENST00000280346.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DLAT	ENST00000280346.11	c.83T>C	p.Val28Ala	missense_variant	1/14	1	NM_001931.5	P3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000479 AC: 7 AN: 1461676 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 727158

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000540

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000282 Hom.: 0

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Feb 04, 2020

Not observed in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.064
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.79
Cadd	Benign	9.8
Dann	Benign	0.57
DEOGEN2	Benign	0.062	T;T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.067	N
LIST_S2	Benign	0.28	T;T
M_CAP	Benign	0.0077	T
MetaRNN	Benign	0.030	T;T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	-0.69	N;.
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-0.17	N;N
REVEL	Benign	0.0090
Sift	Benign	0.88	T;T
Sift4G	Benign	0.74	T;T
Polyphen		0.0	B;B
Vest4		0.066
MVP		0.16
MPC		0.33
ClinPred		0.084	T
GERP RS		-2.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.030
gMVP		0.23

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs1316678815; hg19: chr11-111896279;