rs35560997

Variant names:

• chr11-34978135-G-C
• rs35560997
• NM_003477.3:c.976G>C

Your query was ambiguous. Multiple possible variants found:

• chr11-34978135-G-C
• chr11-34978135-G-A

Variant summary

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

The NM_003477.3(PDHX):​c.976G>C​(p.Val326Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00689 in 1,551,262 control chromosomes in the GnomAD database, including 46 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0057 (4 hom., cov: 32)
  • Exomes 𝑓: 0.0070 (42 hom.)
• Consequence: PDHX NM_003477.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 7.16
• Publications: 12 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]

PDHX Gene-Disease associations (from GenCC):

• Leigh syndrome

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• mitochondrial disease

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• pyruvate dehydrogenase E3-binding protein deficiency

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Ambry Genetics, Labcorp Genetics (formerly Invitae), Genomics England PanelApp, G2P

ACMG classification

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

• BP4: Computational evidence support a benign effect (MetaRNN=0.014632463).
• BP6: Variant 11-34978135-G-C is Benign according to our data. Variant chr11-34978135-G-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 138664.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00574 (874/152212) while in subpopulation NFE AF = 0.00975 (663/67992). AF 95% confidence interval is 0.00914. There are 4 homozygotes in GnomAd4. There are 431 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 4 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003477.3. 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_003477.3	MANE Select	c.976G>C	p.Val326Leu	missense	Exon 8 of 11	NP_003468.2	O00330-1
	PDHX	NM_001135024.2		c.796G>C	p.Val266Leu	missense	Exon 8 of 11	NP_001128496.2	A0A8C8MSB2
	PDHX	NM_001166158.2		c.343-6435G>C		intron	N/A	NP_001159630.1	O00330-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PDHX	ENST00000227868.9	TSL:1 MANE Select	c.976G>C	p.Val326Leu	missense	Exon 8 of 11	ENSP00000227868.4	O00330-1
	PDHX	ENST00000885501.1		c.976G>C	p.Val326Leu	missense	Exon 8 of 12	ENSP00000555560.1
	PDHX	ENST00000952507.1		c.976G>C	p.Val326Leu	missense	Exon 8 of 11	ENSP00000622566.1

Frequencies

GnomAD3 genomes AF: 0.00575 AC: 874 AN: 152094 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.00147

Gnomad AMI AF: 0.00219

Gnomad AMR AF: 0.00387

Gnomad ASJ AF: 0.00519

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00352

Gnomad FIN AF: 0.00415

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00975

Gnomad OTH AF: 0.00383

GnomAD2 exomes AF: 0.00621 AC: 1549 AN: 249402 AF XY: 0.00624

Gnomad AFR exome AF: 0.00155

Gnomad AMR exome AF: 0.00251

Gnomad ASJ exome AF: 0.00429

Gnomad EAS exome AF: 0.000109

Gnomad FIN exome AF: 0.00542

Gnomad NFE exome AF: 0.00996

Gnomad OTH exome AF: 0.00559

GnomAD4 exome AF: 0.00701 AC: 9810 AN: 1399050 Hom.: 42 Cov.: 24 AF XY: 0.00709 AC XY: 4960 AN XY: 699382

African (AFR) AF: 0.00123 AC: 40 AN: 32590

American (AMR) AF: 0.00246 AC: 109 AN: 44382

Ashkenazi Jewish (ASJ) AF: 0.00432 AC: 111 AN: 25696

East Asian (EAS) AF: 0.0000255 AC: 1 AN: 39270

South Asian (SAS) AF: 0.00474 AC: 400 AN: 84426

European-Finnish (FIN) AF: 0.00576 AC: 307 AN: 53338

Middle Eastern (MID) AF: 0.00390 AC: 22 AN: 5642

European-Non Finnish (NFE) AF: 0.00806 AC: 8508 AN: 1055552

Other (OTH) AF: 0.00537 AC: 312 AN: 58154

GnomAD4 genome AF: 0.00574 AC: 874 AN: 152212 Hom.: 4 Cov.: 32 AF XY: 0.00579 AC XY: 431 AN XY: 74440

African (AFR) AF: 0.00147 AC: 61 AN: 41538

American (AMR) AF: 0.00386 AC: 59 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.00519 AC: 18 AN: 3470

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5192

South Asian (SAS) AF: 0.00353 AC: 17 AN: 4822

European-Finnish (FIN) AF: 0.00415 AC: 44 AN: 10604

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

European-Non Finnish (NFE) AF: 0.00975 AC: 663 AN: 67992

Other (OTH) AF: 0.00379 AC: 8 AN: 2112

Alfa AF: 0.00869 Hom.: 11

Bravo AF: 0.00539

TwinsUK AF: 0.0102 AC: 38

ALSPAC AF: 0.00830 AC: 32

ESP6500AA AF: 0.00204 AC: 9

ESP6500EA AF: 0.00886 AC: 76

ExAC AF: 0.00641 AC: 778

Asia WGS AF: 0.00347 AC: 12 AN: 3468

EpiCase AF: 0.00890

EpiControl AF: 0.00853

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	2	not specified (2)
-	-	2	Pyruvate dehydrogenase E3-binding protein deficiency (2)
-	-	1	PDHX-related disorder (1)
-	-	1	Pyruvate dehydrogenase E1-alpha deficiency (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.35
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Uncertain	-0.030
CADD	Uncertain	26
DANN	Benign	0.82
DEOGEN2	Benign	0.28	T
Eigen	Uncertain	0.45
Eigen_PC	Uncertain	0.55
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.93	D
MetaRNN	Benign	0.015	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.77	N
PhyloP100		7.2
PrimateAI	Uncertain	0.58	T
PROVEAN	Benign	-1.8	N
REVEL	Benign	0.20
Sift	Benign	0.30	T
Sift4G	Benign	0.39	T
Polyphen		0.93	P
Vest4		0.61
MutPred		0.58		Loss of methylation at K325 (P = 0.067)
MVP		0.53
MPC		0.25
ClinPred		0.020	T
GERP RS		5.7
PromoterAI		-0.0079	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.29
gMVP		0.72
Mutation Taster		=21/79	disease causing

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: rs35560997; hg19: chr11-34999682; COSMIC: COSV57165211;