3-58427942-G-T

Position:

• chr3-58427942-G-T

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.*92C>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.326 in 960,880 control chromosomes in the GnomAD database, including 55,912 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.29 (7371 hom., cov: 33)
  • Exomes 𝑓: 0.33 (48541 hom.)
• Consequence: PDHB NM_000925.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 2.27

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=-0.9).
• BP6: Variant 3-58427942-G-T is Benign according to our data. Variant chr3-58427942-G-T is described in ClinVar as [Benign]. Clinvar id is 346403.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/exons	MANE	Protein	UniProt
PDHB	NM_000925.4	c.*92C>A		3_prime_UTR_variant	10/10	ENST00000302746.11	NP_000916.2
PDHB	NM_001315536.2	c.*92C>A		3_prime_UTR_variant	9/9		NP_001302465.1
PDHB	NM_001173468.2	c.*92C>A		3_prime_UTR_variant	11/11		NP_001166939.1
PDHB	NR_033384.2	n.1278C>A		non_coding_transcript_exon_variant	9/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PDHB	ENST00000302746	c.*92C>A		3_prime_UTR_variant	10/10	1	NM_000925.4	ENSP00000307241.6

Frequencies

GnomAD3 genomes AF: 0.295 AC: 44779 AN: 151964 Hom.: 7367 Cov.: 33

Gnomad AFR AF: 0.214

Gnomad AMI AF: 0.313

Gnomad AMR AF: 0.311

Gnomad ASJ AF: 0.500

Gnomad EAS AF: 0.00232

Gnomad SAS AF: 0.203

Gnomad FIN AF: 0.237

Gnomad MID AF: 0.392

Gnomad NFE AF: 0.365

Gnomad OTH AF: 0.340

GnomAD3 exomes AF: 0.291 AC: 49825 AN: 171432 Hom.: 8455 AF XY: 0.292 AC XY: 27070 AN XY: 92568

Gnomad AFR exome AF: 0.209

Gnomad AMR exome AF: 0.253

Gnomad ASJ exome AF: 0.491

Gnomad EAS exome AF: 0.00123

Gnomad SAS exome AF: 0.226

Gnomad FIN exome AF: 0.239

Gnomad NFE exome AF: 0.371

Gnomad OTH exome AF: 0.333

GnomAD4 exome AF: 0.332 AC: 268251 AN: 808798 Hom.: 48541 Cov.: 11 AF XY: 0.329 AC XY: 139605 AN XY: 423850

Gnomad4 AFR exome AF: 0.204

Gnomad4 AMR exome AF: 0.260

Gnomad4 ASJ exome AF: 0.492

Gnomad4 EAS exome AF: 0.000784

Gnomad4 SAS exome AF: 0.232

Gnomad4 FIN exome AF: 0.236

Gnomad4 NFE exome AF: 0.375

Gnomad4 OTH exome AF: 0.330

GnomAD4 genome AF: 0.295 AC: 44804 AN: 152082 Hom.: 7371 Cov.: 33 AF XY: 0.285 AC XY: 21156 AN XY: 74344

Gnomad4 AFR AF: 0.214

Gnomad4 AMR AF: 0.310

Gnomad4 ASJ AF: 0.500

Gnomad4 EAS AF: 0.00252

Gnomad4 SAS AF: 0.205

Gnomad4 FIN AF: 0.237

Gnomad4 NFE AF: 0.365

Gnomad4 OTH AF: 0.336

Alfa AF: 0.308 Hom.: 1948

Bravo AF: 0.297

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

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Pyruvate dehydrogenase E1-beta deficiency Benign:1

Benign, 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 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	-0.90
CADD	Benign	6.6
DANN	Benign	0.45

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: rs4228; hg19: chr3-58413669;