rs1555179245

Variant names:

• chr11-112026273-A-C
• rs1555179245
• NM_001931.5:c.355A>C

Your query was ambiguous. Multiple possible variants found:

• chr11-112026273-A-C
• chr11-112026273-A-G

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001931.5(DLAT):​c.355A>C​(p.Ile119Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000659 in 151,712 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. I119V) has been classified as Uncertain significance.

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
• Consequence: DLAT NM_001931.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.62
• 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: Orphanet, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P
• Leigh syndrome

  Inheritance: AR Classification: MODERATE Submitted by: ClinGen

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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.355A>C	p.Ile119Leu	missense	Exon 2 of 14	NP_001922.2
	DLAT	NM_001372031.1		c.355A>C	p.Ile119Leu	missense	Exon 2 of 14	NP_001358960.1
	DLAT	NM_001372032.1		c.355A>C	p.Ile119Leu	missense	Exon 2 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.355A>C	p.Ile119Leu	missense	Exon 2 of 14	ENSP00000280346.7
	DLAT	ENST00000713569.1		c.355A>C	p.Ile119Leu	missense	Exon 2 of 14	ENSP00000518862.1
	DLAT	ENST00000681316.1		c.355A>C	p.Ile119Leu	missense	Exon 2 of 14	ENSP00000506560.1

Frequencies

GnomAD3 genomes AF: 0.00000659 AC: 1 AN: 151712 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 31

GnomAD4 genome AF: 0.00000659 AC: 1 AN: 151712 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74090

African (AFR) AF: 0.0000242 AC: 1 AN: 41248

American (AMR) AF: 0.00 AC: 0 AN: 15246

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5194

South Asian (SAS) AF: 0.00 AC: 0 AN: 4802

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10492

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67956

Other (OTH) AF: 0.00 AC: 0 AN: 2076

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.27
BayesDel_addAF	Uncertain	0.027	T
BayesDel_noAF	Benign	-0.20
CADD	Benign	22
DANN	Benign	0.95
DEOGEN2	Benign	0.092	T
Eigen	Benign	-0.10
Eigen_PC	Benign	0.11
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.95	D
M_CAP	Benign	0.043	D
MetaRNN	Uncertain	0.51	D
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.28	N
PhyloP100		6.6
PrimateAI	Uncertain	0.75	T
PROVEAN	Benign	-0.63	N
REVEL	Benign	0.20
Sift	Benign	0.82	T
Sift4G	Benign	0.13	T
Polyphen		0.54	P
Vest4		0.53
MutPred		0.79		Gain of sheet (P = 0.0344)
MVP		0.63
MPC		0.50
ClinPred		0.83	D
GERP RS		4.7
PromoterAI		0.017	Neutral
Varity_R		0.19
gMVP		0.66
Mutation Taster		=83/17	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: rs1555179245; hg19: chr11-111896997;