chr11-112025316-G-A

Variant names:

• chr11-112025316-G-A
• rs587688778
• ENST00000713569.1:c.-157G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The ENST00000713569.1(DLAT):​c.-157G>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00228 in 1,022,826 control chromosomes in the GnomAD database, including 19 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0090 (10 hom., cov: 33)
  • Exomes 𝑓: 0.0011 (9 hom.)
• Consequence: DLAT ENST00000713569.1 5_prime_UTR
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.648
• 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.77).
• BP6: Variant 11-112025316-G-A is Benign according to our data. Variant chr11-112025316-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 1210737.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00897 (1367/152344) while in subpopulation AFR AF = 0.0301 (1253/41584). AF 95% confidence interval is 0.0287. There are 10 homozygotes in GnomAd4. There are 648 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 10 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000713569.1. 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.-157G>A		upstream_gene	N/A	NP_001922.2
	DLAT	NM_001372031.1		c.-157G>A		upstream_gene	N/A	NP_001358960.1
	DLAT	NM_001372032.1		c.-157G>A		upstream_gene	N/A	NP_001358961.1	A0A7P0TBE2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DLAT	ENST00000713569.1		c.-157G>A		5_prime_UTR	Exon 1 of 14	ENSP00000518862.1	P10515
	DLAT	ENST00000280346.11	TSL:1 MANE Select	c.-157G>A		upstream_gene	N/A	ENSP00000280346.7	P10515
	DLAT	ENST00000915657.1		c.-157G>A		upstream_gene	N/A	ENSP00000585716.1

Frequencies

GnomAD3 genomes AF: 0.00895 AC: 1363 AN: 152226 Hom.: 10 Cov.: 33

Gnomad AFR AF: 0.0301

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00523

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000191

Gnomad OTH AF: 0.00955

GnomAD4 exome AF: 0.00111 AC: 970 AN: 870482 Hom.: 9 Cov.: 12 AF XY: 0.00100 AC XY: 441 AN XY: 439336

African (AFR) AF: 0.0339 AC: 735 AN: 21682

American (AMR) AF: 0.00210 AC: 65 AN: 30990

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18442

East Asian (EAS) AF: 0.00 AC: 0 AN: 33172

South Asian (SAS) AF: 0.000198 AC: 12 AN: 60630

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 32152

Middle Eastern (MID) AF: 0.00340 AC: 10 AN: 2944

European-Non Finnish (NFE) AF: 0.0000730 AC: 46 AN: 630244

Other (OTH) AF: 0.00254 AC: 102 AN: 40226

GnomAD4 genome AF: 0.00897 AC: 1367 AN: 152344 Hom.: 10 Cov.: 33 AF XY: 0.00870 AC XY: 648 AN XY: 74498

African (AFR) AF: 0.0301 AC: 1253 AN: 41584

American (AMR) AF: 0.00522 AC: 80 AN: 15312

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000191 AC: 13 AN: 68030

Other (OTH) AF: 0.00945 AC: 20 AN: 2116

Alfa AF: 0.00867 Hom.: 2

Bravo AF: 0.0104

Asia WGS AF: 0.00289 AC: 10 AN: 3478

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
CADD	Benign	2.1
DANN	Benign	0.72
PhyloP100		-0.65
PromoterAI		0.057	Neutral
Mutation Taster		=300/0	polymorphism

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: rs587688778; hg19: chr11-111896040;