rs377063331

chr3-58429802-G-A

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 2P and 3B. PM2 BP4_Moderate BP6

The NM_000925.4(PDHB):c.701-3C>T variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000636 in 1,572,778 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00052 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00065 (1 hom.)
• Consequence: PDHB NM_000925.4 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.1155
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:2
• Conservation: PhyloP100: 2.84

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]

ACMG classification

Verdict is Likely_benign. Variant got -1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.31).
• BP6: Variant 3-58429802-G-A is Benign according to our data. Variant chr3-58429802-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 346406.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=2, Benign=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PDHB	NM_000925.4	c.701-3C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000302746.11
PDHB	NM_001173468.2	c.647-3C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant
PDHB	NM_001315536.2	c.647-3C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant
PDHB	NR_033384.2	n.807-3C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PDHB	ENST00000302746.11	c.701-3C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_000925.4	P1

Frequencies

GnomAD3 genomes AF: 0.000519 AC: 79 AN: 152184 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000265

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000622

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000911

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000414 AC: 104 AN: 251430 Hom.: 0 AF XY: 0.000405 AC XY: 55 AN XY: 135882

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.000145

Gnomad ASJ exome AF: 0.0000992

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000294

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.000703

Gnomad OTH exome AF: 0.00114

GnomAD4 exome AF: 0.000648 AC: 921 AN: 1420476 Hom.: 1 Cov.: 25 AF XY: 0.000639 AC XY: 453 AN XY: 709432

Gnomad4 AFR exome AF: 0.0000612

Gnomad4 AMR exome AF: 0.000157

Gnomad4 ASJ exome AF: 0.0000386

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000351

Gnomad4 FIN exome AF: 0.0000936

Gnomad4 NFE exome AF: 0.000776

Gnomad4 OTH exome AF: 0.000627

GnomAD4 genome AF: 0.000519 AC: 79 AN: 152302 Hom.: 0 Cov.: 32 AF XY: 0.000403 AC XY: 30 AN XY: 74452

Gnomad4 AFR AF: 0.000265

Gnomad4 AMR AF: 0.000196

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000622

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000911

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000809 Hom.: 0

Bravo AF: 0.000480

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000545

EpiControl AF: 0.000533

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Pyruvate dehydrogenase E1-beta deficiency Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Sep 29, 2022	This sequence change falls in intron 7 of the PDHB gene. It does not directly change the encoded amino acid sequence of the PDHB protein. It affects a nucleotide within the consensus splice site. This variant is present in population databases (rs377063331, gnomAD 0.08%), and has an allele count higher than expected for a pathogenic variant. This variant has not been reported in the literature in individuals affected with PDHB-related conditions. ClinVar contains an entry for this variant (Variation ID: 346406). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant is not likely to affect RNA splicing. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2023	PDHB: BP4 -

Pyruvate dehydrogenase complex deficiency Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Natera, Inc.

Jun 05, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.31
Cadd	Benign	16
Dann	Benign	0.88

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.12
dbscSNV1_RF	Benign	0.056
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs377063331; hg19: chr3-58415529;