3-58427678-T-C

Position:

• chr3-58427678-T-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.*356A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.28 in 389,678 control chromosomes in the GnomAD database, including 19,228 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.24 (6016 hom., cov: 32)
  • Exomes 𝑓: 0.31 (13212 hom.)
• Consequence: PDHB NM_000925.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.27

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.68).
• BP6: Variant 3-58427678-T-C is Benign according to our data. Variant chr3-58427678-T-C is described in ClinVar as [Benign]. Clinvar id is 346397.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.784 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PDHB	NM_000925.4	c.*356A>G		3_prime_UTR_variant	10/10	ENST00000302746.11	NP_000916.2
PDHB	NM_001315536.2	c.*356A>G		3_prime_UTR_variant	9/9		NP_001302465.1
PDHB	NM_001173468.2	c.*356A>G		3_prime_UTR_variant	11/11		NP_001166939.1
PDHB	NR_033384.2	n.1542A>G		non_coding_transcript_exon_variant	9/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PDHB	ENST00000302746	c.*356A>G		3_prime_UTR_variant	10/10	1	NM_000925.4	ENSP00000307241.6

Frequencies

GnomAD3 genomes AF: 0.239 AC: 36231 AN: 151840 Hom.: 6017 Cov.: 32

Gnomad AFR AF: 0.0753

Gnomad AMI AF: 0.398

Gnomad AMR AF: 0.308

Gnomad ASJ AF: 0.152

Gnomad EAS AF: 0.805

Gnomad SAS AF: 0.449

Gnomad FIN AF: 0.312

Gnomad MID AF: 0.213

Gnomad NFE AF: 0.255

Gnomad OTH AF: 0.253

GnomAD3 exomes AF: 0.326 AC: 28010 AN: 86020 Hom.: 6103 AF XY: 0.328 AC XY: 15436 AN XY: 47010

Gnomad AFR exome AF: 0.0715

Gnomad AMR exome AF: 0.318

Gnomad ASJ exome AF: 0.159

Gnomad EAS exome AF: 0.818

Gnomad SAS exome AF: 0.400

Gnomad FIN exome AF: 0.317

Gnomad NFE exome AF: 0.249

Gnomad OTH exome AF: 0.300

GnomAD4 exome AF: 0.306 AC: 72723 AN: 237720 Hom.: 13212 Cov.: 0 AF XY: 0.314 AC XY: 41950 AN XY: 133556

Gnomad4 AFR exome AF: 0.0765

Gnomad4 AMR exome AF: 0.319

Gnomad4 ASJ exome AF: 0.151

Gnomad4 EAS exome AF: 0.815

Gnomad4 SAS exome AF: 0.388

Gnomad4 FIN exome AF: 0.330

Gnomad4 NFE exome AF: 0.259

Gnomad4 OTH exome AF: 0.294

GnomAD4 genome AF: 0.238 AC: 36239 AN: 151958 Hom.: 6016 Cov.: 32 AF XY: 0.250 AC XY: 18556 AN XY: 74234

Gnomad4 AFR AF: 0.0753

Gnomad4 AMR AF: 0.308

Gnomad4 ASJ AF: 0.152

Gnomad4 EAS AF: 0.804

Gnomad4 SAS AF: 0.447

Gnomad4 FIN AF: 0.312

Gnomad4 NFE AF: 0.255

Gnomad4 OTH AF: 0.260

Alfa AF: 0.238 Hom.: 2224

Bravo AF: 0.227

Asia WGS AF: 0.588 AC: 2044 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Pyruvate dehydrogenase E1-beta deficiency Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 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 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. -

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.68
CADD	Benign	15
DANN	Benign	0.87

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: rs1126737; hg19: chr3-58413405;