rs119103240

Variant names:

• chr11-112061088-C-A
• rs119103240
• NM_001931.5:c.1728C>A

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM2 PP3_Strong PP5

The NM_001931.5(DLAT):​c.1728C>A​(p.Phe576Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000411 in 1,461,172 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: DLAT NM_001931.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3 U:1
• Conservation: PhyloP100: 1.94
• Publications: 1 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]

PIH1D2 (HGNC:25210): (PIH1 domain containing 2) Enables small GTPase binding activity. Predicted to be involved in box C/D snoRNP assembly and rRNA processing. Predicted to be part of R2TP complex and ribonucleoprotein complex. Predicted to be active in cytoplasm. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Likely_pathogenic. The variant received 7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.969
• PP5: Variant 11-112061088-C-A is Pathogenic according to our data. Variant chr11-112061088-C-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 2110.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DLAT	NM_001931.5	MANE Select	c.1728C>A	p.Phe576Leu	missense	Exon 13 of 14	NP_001922.2
	DLAT	NM_001372031.1		c.1746C>A	p.Phe582Leu	missense	Exon 13 of 14	NP_001358960.1
	DLAT	NM_001372032.1		c.1722C>A	p.Phe574Leu	missense	Exon 13 of 14	NP_001358961.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DLAT	ENST00000280346.11	TSL:1 MANE Select	c.1728C>A	p.Phe576Leu	missense	Exon 13 of 14	ENSP00000280346.7
	DLAT	ENST00000713569.1		c.1728C>A	p.Phe576Leu	missense	Exon 13 of 14	ENSP00000518862.1
	DLAT	ENST00000681316.1		c.1722C>A	p.Phe574Leu	missense	Exon 13 of 14	ENSP00000506560.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000120 AC: 3 AN: 250540 AF XY: 0.0000222

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000883

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000411 AC: 6 AN: 1461172 Hom.: 0 Cov.: 30 AF XY: 0.00000550 AC XY: 4 AN XY: 726876

African (AFR) AF: 0.00 AC: 0 AN: 33458

American (AMR) AF: 0.00 AC: 0 AN: 44686

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26114

East Asian (EAS) AF: 0.00 AC: 0 AN: 39664

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86136

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53378

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

European-Non Finnish (NFE) AF: 0.00000270 AC: 3 AN: 1111604

Other (OTH) AF: 0.00 AC: 0 AN: 60364

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
3	1	-	Pyruvate dehydrogenase E2 deficiency (4)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Pathogenic	0.15
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.47	T
Eigen	Uncertain	0.38
Eigen_PC	Uncertain	0.24
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Uncertain	0.10	D
MetaRNN	Pathogenic	0.97	D
MetaSVM	Uncertain	-0.061	T
MutationAssessor	Pathogenic	4.0	H
PhyloP100		1.9
PrimateAI	Pathogenic	0.86	D
PROVEAN	Pathogenic	-5.9	D
REVEL	Uncertain	0.59
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.0050	D
Polyphen		0.99	D
Vest4		0.93
MutPred		0.98		Gain of ubiquitination at K574 (P = 0.1679)
MVP		0.57
MPC		1.0
ClinPred		0.99	D
GERP RS		0.84
Varity_R		0.90
gMVP		0.87
Mutation Taster		=3/97	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs119103240; hg19: chr11-111931812;