3-58427791-T-G

Variant names:

• chr3-58427791-T-G
• rs1126722
• NM_000925.4:c.*243A>C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000925.4(PDHB):​c.*243A>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.309 in 568,728 control chromosomes in the GnomAD database, including 30,469 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.29 (7260 hom., cov: 32)
  • Exomes 𝑓: 0.32 (23209 hom.)
• Consequence: PDHB NM_000925.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.316

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 3-58427791-T-G is Benign according to our data. Variant chr3-58427791-T-G is described in ClinVar as [Benign]. Clinvar id is 346400.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.361 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PDHB	NM_000925.4	c.*243A>C		3_prime_UTR_variant	Exon 10 of 10	ENST00000302746.11	NP_000916.2
PDHB	NM_001315536.2	c.*243A>C		3_prime_UTR_variant	Exon 9 of 9		NP_001302465.1
PDHB	NM_001173468.2	c.*243A>C		3_prime_UTR_variant	Exon 11 of 11		NP_001166939.1
PDHB	NR_033384.2	n.1429A>C		non_coding_transcript_exon_variant	Exon 9 of 9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PDHB	ENST00000302746	c.*243A>C		3_prime_UTR_variant	Exon 10 of 10	1	NM_000925.4	ENSP00000307241.6

Frequencies

GnomAD3 genomes AF: 0.292 AC: 44325 AN: 151972 Hom.: 7257 Cov.: 32

Gnomad AFR AF: 0.204

Gnomad AMI AF: 0.314

Gnomad AMR AF: 0.310

Gnomad ASJ AF: 0.500

Gnomad EAS AF: 0.00231

Gnomad SAS AF: 0.204

Gnomad FIN AF: 0.237

Gnomad MID AF: 0.392

Gnomad NFE AF: 0.365

Gnomad OTH AF: 0.338

GnomAD3 exomes AF: 0.290 AC: 38080 AN: 131234 Hom.: 6512 AF XY: 0.291 AC XY: 20842 AN XY: 71568

Gnomad AFR exome AF: 0.201

Gnomad AMR exome AF: 0.256

Gnomad ASJ exome AF: 0.494

Gnomad EAS exome AF: 0.00105

Gnomad SAS exome AF: 0.229

Gnomad FIN exome AF: 0.231

Gnomad NFE exome AF: 0.375

Gnomad OTH exome AF: 0.343

GnomAD4 exome AF: 0.315 AC: 131414 AN: 416638 Hom.: 23209 Cov.: 0 AF XY: 0.313 AC XY: 72170 AN XY: 230230

Gnomad4 AFR exome AF: 0.195

Gnomad4 AMR exome AF: 0.259

Gnomad4 ASJ exome AF: 0.496

Gnomad4 EAS exome AF: 0.000886

Gnomad4 SAS exome AF: 0.233

Gnomad4 FIN exome AF: 0.237

Gnomad4 NFE exome AF: 0.368

Gnomad4 OTH exome AF: 0.329

GnomAD4 genome AF: 0.292 AC: 44348 AN: 152090 Hom.: 7260 Cov.: 32 AF XY: 0.282 AC XY: 20945 AN XY: 74344

Gnomad4 AFR AF: 0.204

Gnomad4 AMR AF: 0.309

Gnomad4 ASJ AF: 0.500

Gnomad4 EAS AF: 0.00251

Gnomad4 SAS AF: 0.205

Gnomad4 FIN AF: 0.237

Gnomad4 NFE AF: 0.365

Gnomad4 OTH AF: 0.334

Alfa AF: 0.371 Hom.: 10393

Bravo AF: 0.293

Asia WGS AF: 0.0980 AC: 343 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jun 23, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Pyruvate dehydrogenase E1-beta deficiency Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	3.1
DANN	Benign	0.59
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0

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

Publications

LitVar

Other links and lift over

dbSNP: rs1126722; hg19: chr3-58413518;