NM_000925.4:c.*366_*367insAA

Variant names:

• chr3-58427667-C-CTT
• rs886058775
• NM_000925.4:c.*366_*367insAA

Variant summary

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

The NM_000925.4(PDHB):​c.*366_*367insAA variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000457 in 218,980 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000046 (0 hom.)
• Consequence: PDHB NM_000925.4 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.211
• Publications: 0 publications found

Genes affected

PDHB (HGNC:8808): (pyruvate dehydrogenase E1 subunit beta) The pyruvate dehydrogenase (PDH) complex is a nuclear-encoded mitochondrial multienzyme complex that catalyzes the overall conversion of pyruvate to acetyl-CoA and carbon dioxide, and provides the primary link between glycolysis and the tricarboxylic acid (TCA) cycle. The PDH complex is composed of multiple copies of three enzymatic components: pyruvate dehydrogenase (E1), dihydrolipoamide acetyltransferase (E2) and lipoamide dehydrogenase (E3). The E1 enzyme is a heterotetramer of two alpha and two beta subunits. This gene encodes the E1 beta subunit. Mutations in this gene are associated with pyruvate dehydrogenase E1-beta deficiency. Alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Mar 2012]

PDHB Gene-Disease associations (from GenCC):

• pyruvate dehydrogenase E1-beta deficiency

  Inheritance: AR Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Orphanet, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Ambry Genetics
• 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_000925.4. 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
	PDHB	NM_000925.4	MANE Select	c.*366_*367insAA		3_prime_UTR	Exon 10 of 10	NP_000916.2	A0A384MDR8
	PDHB	NM_001173468.2		c.*366_*367insAA		3_prime_UTR	Exon 11 of 11	NP_001166939.1	P11177-3
	PDHB	NM_001315536.2		c.*366_*367insAA		3_prime_UTR	Exon 9 of 9	NP_001302465.1	P11177-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PDHB	ENST00000302746.11	TSL:1 MANE Select	c.*366_*367insAA		3_prime_UTR	Exon 10 of 10	ENSP00000307241.6	P11177-1
	PDHB	ENST00000383714.8	TSL:1	c.*366_*367insAA		3_prime_UTR	Exon 9 of 9	ENSP00000373220.4	P11177-2
	PDHB	ENST00000962538.1		c.*366_*367insAA		3_prime_UTR	Exon 10 of 10	ENSP00000632597.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.0000136 AC: 1 AN: 73796 AF XY: 0.0000249

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000127

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000457 AC: 1 AN: 218980 Hom.: 0 Cov.: 0 AF XY: 0.00000814 AC XY: 1 AN XY: 122872

African (AFR) AF: 0.00 AC: 0 AN: 5302

American (AMR) AF: 0.00 AC: 0 AN: 12074

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 6220

East Asian (EAS) AF: 0.000120 AC: 1 AN: 8314

South Asian (SAS) AF: 0.00 AC: 0 AN: 44574

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9586

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 121824

Other (OTH) AF: 0.00 AC: 0 AN: 10318

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Pyruvate dehydrogenase complex deficiency (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.21

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs886058775; hg19: chr3-58413394;