11-112062954-A-G

Variant names:

• chr11-112062954-A-G
• rs9371
• NM_001931.5:c.*419A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001931.5(DLAT):​c.*419A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.497 in 165,156 control chromosomes in the GnomAD database, including 22,935 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.51 (21768 hom., cov: 32)
  • Exomes 𝑓: 0.40 (1167 hom.)
• Consequence: DLAT NM_001931.5 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0980
• Publications: 9 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.77 is higher than 0.05.

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.*419A>G		3_prime_UTR	Exon 14 of 14	NP_001922.2
	DLAT	NR_164072.1		n.2240A>G		non_coding_transcript_exon	Exon 13 of 13
	DLAT	NM_001372031.1		c.*419A>G		3_prime_UTR	Exon 14 of 14	NP_001358960.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DLAT	ENST00000280346.11	TSL:1 MANE Select	c.*419A>G		3_prime_UTR	Exon 14 of 14	ENSP00000280346.7
	DLAT	ENST00000527231.2	TSL:5	n.3641A>G		non_coding_transcript_exon	Exon 13 of 13
	DLAT	ENST00000679368.1		n.*1290A>G		non_coding_transcript_exon	Exon 13 of 13	ENSP00000505314.1

Frequencies

GnomAD3 genomes AF: 0.506 AC: 76813 AN: 151930 Hom.: 21714 Cov.: 32

Gnomad AFR AF: 0.777

Gnomad AMI AF: 0.548

Gnomad AMR AF: 0.421

Gnomad ASJ AF: 0.301

Gnomad EAS AF: 0.583

Gnomad SAS AF: 0.419

Gnomad FIN AF: 0.447

Gnomad MID AF: 0.443

Gnomad NFE AF: 0.381

Gnomad OTH AF: 0.447

GnomAD4 exome AF: 0.400 AC: 5240 AN: 13108 Hom.: 1167 Cov.: 0 AF XY: 0.404 AC XY: 2859 AN XY: 7082

African (AFR) AF: 0.770 AC: 137 AN: 178

American (AMR) AF: 0.431 AC: 892 AN: 2072

Ashkenazi Jewish (ASJ) AF: 0.323 AC: 84 AN: 260

East Asian (EAS) AF: 0.549 AC: 413 AN: 752

South Asian (SAS) AF: 0.424 AC: 716 AN: 1688

European-Finnish (FIN) AF: 0.359 AC: 94 AN: 262

Middle Eastern (MID) AF: 0.292 AC: 7 AN: 24

European-Non Finnish (NFE) AF: 0.367 AC: 2684 AN: 7322

Other (OTH) AF: 0.387 AC: 213 AN: 550

GnomAD4 genome AF: 0.506 AC: 76925 AN: 152048 Hom.: 21768 Cov.: 32 AF XY: 0.509 AC XY: 37838 AN XY: 74288

African (AFR) AF: 0.777 AC: 32252 AN: 41510

American (AMR) AF: 0.421 AC: 6425 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.301 AC: 1045 AN: 3468

East Asian (EAS) AF: 0.583 AC: 3014 AN: 5166

South Asian (SAS) AF: 0.418 AC: 2016 AN: 4820

European-Finnish (FIN) AF: 0.447 AC: 4709 AN: 10540

Middle Eastern (MID) AF: 0.456 AC: 134 AN: 294

European-Non Finnish (NFE) AF: 0.381 AC: 25886 AN: 67960

Other (OTH) AF: 0.447 AC: 944 AN: 2110

Alfa AF: 0.434 Hom.: 6650

Bravo AF: 0.520

Asia WGS AF: 0.480 AC: 1671 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	2.7
DANN	Benign	0.60
PhyloP100		-0.098
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Mutation Taster		=100/0	polymorphism (auto)

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: rs9371; hg19: chr11-111933678;