11-34916454-A-G

Variant names:

• chr11-34916454-A-G
• rs113073242
• NM_001135024.2:c.-53A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001135024.2(PDHX):​c.-53A>G variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.126 in 1,465,234 control chromosomes in the GnomAD database, including 14,529 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.19 (3876 hom., cov: 32)
  • Exomes 𝑓: 0.12 (10653 hom.)
• Consequence: PDHX NM_001135024.2 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.278
• Publications: 16 publications found

Genes affected

PDHX (HGNC:21350): (pyruvate dehydrogenase complex component X) The pyruvate dehydrogenase (PDH) complex is located in the mitochondrial matrix and catalyzes the conversion of pyruvate to acetyl coenzyme A. The PDH complex thereby links glycolysis to Krebs cycle. The PDH complex contains three catalytic subunits, E1, E2, and E3, two regulatory subunits, E1 kinase and E1 phosphatase, and a non-catalytic subunit, E3 binding protein (E3BP). This gene encodes the E3 binding protein subunit; also known as component X of the pyruvate dehydrogenase complex. This protein tethers E3 dimers to the E2 core of the PDH complex. Defects in this gene are a cause of pyruvate dehydrogenase deficiency which results in neurological dysfunction and lactic acidosis in infancy and early childhood. This protein is also a minor 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 eventually leads to cirrhosis and liver failure. Alternative splicing results in multiple transcript variants encoding distinct isoforms.[provided by RefSeq, Oct 2009]

APIP (HGNC:17581): (APAF1 interacting protein) Enables identical protein binding activity; methylthioribulose 1-phosphate dehydratase activity; and zinc ion binding activity. Involved in several processes, including L-methionine salvage from methylthioadenosine; protein homotetramerization; and pyroptosis. Located in cytoplasm. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=6.676316E-4).
• BP6: Variant 11-34916454-A-G is Benign according to our data. Variant chr11-34916454-A-G is described in ClinVar as Benign. ClinVar VariationId is 304454.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.386 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001135024.2. 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
	PDHX	NM_001135024.2		c.-53A>G		5_prime_UTR	Exon 1 of 11	NP_001128496.2	A0A8C8MSB2
	PDHX	NM_003477.3	MANE Select	c.-202A>G		upstream_gene	N/A	NP_003468.2	O00330-1
	APIP	NM_015957.4	MANE Select	c.-170T>C		upstream_gene	N/A	NP_057041.2	Q96GX9-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PDHX	ENST00000448838.8	TSL:5	c.-53A>G		5_prime_UTR	Exon 1 of 11	ENSP00000389404.3	A0A8C8MSB2
	APIP	ENST00000937716.1		c.-170T>C		5_prime_UTR	Exon 1 of 7	ENSP00000607775.1
	APIP	ENST00000901544.1		c.-170T>C		5_prime_UTR	Exon 1 of 6	ENSP00000571603.1

Frequencies

GnomAD3 genomes AF: 0.189 AC: 28665 AN: 151474 Hom.: 3869 Cov.: 32

Gnomad AFR AF: 0.391

Gnomad AMI AF: 0.0373

Gnomad AMR AF: 0.110

Gnomad ASJ AF: 0.148

Gnomad EAS AF: 0.0861

Gnomad SAS AF: 0.114

Gnomad FIN AF: 0.117

Gnomad MID AF: 0.139

Gnomad NFE AF: 0.114

Gnomad OTH AF: 0.179

GnomAD2 exomes AF: 0.125 AC: 9758 AN: 78302 AF XY: 0.122

Gnomad AFR exome AF: 0.403

Gnomad AMR exome AF: 0.0818

Gnomad ASJ exome AF: 0.145

Gnomad EAS exome AF: 0.0949

Gnomad FIN exome AF: 0.110

Gnomad NFE exome AF: 0.108

Gnomad OTH exome AF: 0.111

GnomAD4 exome AF: 0.118 AC: 155343 AN: 1313648 Hom.: 10653 Cov.: 40 AF XY: 0.118 AC XY: 75583 AN XY: 639870

African (AFR) AF: 0.398 AC: 11543 AN: 29012

American (AMR) AF: 0.0894 AC: 2152 AN: 24066

Ashkenazi Jewish (ASJ) AF: 0.149 AC: 2946 AN: 19736

East Asian (EAS) AF: 0.0962 AC: 3374 AN: 35066

South Asian (SAS) AF: 0.117 AC: 7793 AN: 66802

European-Finnish (FIN) AF: 0.115 AC: 4383 AN: 38178

Middle Eastern (MID) AF: 0.146 AC: 625 AN: 4286

European-Non Finnish (NFE) AF: 0.111 AC: 115525 AN: 1042192

Other (OTH) AF: 0.129 AC: 7002 AN: 54310

GnomAD4 genome AF: 0.189 AC: 28705 AN: 151586 Hom.: 3876 Cov.: 32 AF XY: 0.186 AC XY: 13810 AN XY: 74072

African (AFR) AF: 0.391 AC: 16132 AN: 41282

American (AMR) AF: 0.110 AC: 1680 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.148 AC: 511 AN: 3464

East Asian (EAS) AF: 0.0862 AC: 441 AN: 5118

South Asian (SAS) AF: 0.115 AC: 551 AN: 4812

European-Finnish (FIN) AF: 0.117 AC: 1229 AN: 10492

Middle Eastern (MID) AF: 0.133 AC: 39 AN: 294

European-Non Finnish (NFE) AF: 0.114 AC: 7714 AN: 67846

Other (OTH) AF: 0.178 AC: 374 AN: 2100

Alfa AF: 0.132 Hom.: 2370

Bravo AF: 0.199

TwinsUK AF: 0.120 AC: 445

ALSPAC AF: 0.115 AC: 442

ExAC AF: 0.0415 AC: 2593

Asia WGS AF: 0.0890 AC: 307 AN: 3476

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Pyruvate dehydrogenase E3-binding protein deficiency (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.073
BayesDel_addAF	Benign	-0.73	T
BayesDel_noAF	Benign	-0.67
CADD	Benign	9.0
DANN	Benign	0.55
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.00069	N
LIST_S2	Benign	0.17	T
MetaRNN	Benign	0.00067	T
MetaSVM	Benign	-0.90	T
PhyloP100		0.28
PROVEAN	Benign	-0.55	N
REVEL	Benign	0.0050
Sift	Benign	0.54	T
Sift4G	Benign	0.34	T
Vest4		0.025
ClinPred		0.0020	T
GERP RS		-0.37
PromoterAI		0.022	Neutral
Mutation Taster		=99/1	polymorphism (auto)

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: rs113073242; hg19: chr11-34938001; COSMIC: COSV53505903; COSMIC: COSV53505903;