3-58427935-G-A

Position:

• chr3-58427935-G-A

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.*99C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.282 in 914,662 control chromosomes in the GnomAD database, including 44,437 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.24 (6050 hom., cov: 33)
  • Exomes 𝑓: 0.29 (38387 hom.)
• Consequence: PDHB NM_000925.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.0940

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=-0.88).
• BP6: Variant 3-58427935-G-A is Benign according to our data. Variant chr3-58427935-G-A is described in ClinVar as [Benign]. Clinvar id is 346402.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.783 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PDHB	NM_000925.4	c.*99C>T		3_prime_UTR_variant	10/10	ENST00000302746.11	NP_000916.2
PDHB	NM_001315536.2	c.*99C>T		3_prime_UTR_variant	9/9		NP_001302465.1
PDHB	NM_001173468.2	c.*99C>T		3_prime_UTR_variant	11/11		NP_001166939.1
PDHB	NR_033384.2	n.1285C>T		non_coding_transcript_exon_variant	9/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PDHB	ENST00000302746	c.*99C>T		3_prime_UTR_variant	10/10	1	NM_000925.4	ENSP00000307241.6

Frequencies

GnomAD3 genomes AF: 0.239 AC: 36334 AN: 152036 Hom.: 6051 Cov.: 33

Gnomad AFR AF: 0.0753

Gnomad AMI AF: 0.397

Gnomad AMR AF: 0.308

Gnomad ASJ AF: 0.151

Gnomad EAS AF: 0.804

Gnomad SAS AF: 0.448

Gnomad FIN AF: 0.314

Gnomad MID AF: 0.220

Gnomad NFE AF: 0.256

Gnomad OTH AF: 0.253

GnomAD3 exomes AF: 0.320 AC: 51907 AN: 162346 Hom.: 10641 AF XY: 0.324 AC XY: 28298 AN XY: 87356

Gnomad AFR exome AF: 0.0716

Gnomad AMR exome AF: 0.334

Gnomad ASJ exome AF: 0.158

Gnomad EAS exome AF: 0.817

Gnomad SAS exome AF: 0.393

Gnomad FIN exome AF: 0.325

Gnomad NFE exome AF: 0.254

Gnomad OTH exome AF: 0.285

GnomAD4 exome AF: 0.290 AC: 221379 AN: 762508 Hom.: 38387 Cov.: 10 AF XY: 0.294 AC XY: 117774 AN XY: 400860

Gnomad4 AFR exome AF: 0.0722

Gnomad4 AMR exome AF: 0.329

Gnomad4 ASJ exome AF: 0.153

Gnomad4 EAS exome AF: 0.784

Gnomad4 SAS exome AF: 0.389

Gnomad4 FIN exome AF: 0.325

Gnomad4 NFE exome AF: 0.254

Gnomad4 OTH exome AF: 0.281

GnomAD4 genome AF: 0.239 AC: 36342 AN: 152154 Hom.: 6050 Cov.: 33 AF XY: 0.251 AC XY: 18638 AN XY: 74376

Gnomad4 AFR AF: 0.0753

Gnomad4 AMR AF: 0.308

Gnomad4 ASJ AF: 0.151

Gnomad4 EAS AF: 0.803

Gnomad4 SAS AF: 0.447

Gnomad4 FIN AF: 0.314

Gnomad4 NFE AF: 0.256

Gnomad4 OTH AF: 0.261

Alfa AF: 0.238 Hom.: 1733

Bravo AF: 0.227

Asia WGS AF: 0.588 AC: 2043 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 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. -

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	-0.88
CADD	Benign	3.0
DANN	Benign	0.60

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: rs7230; hg19: chr3-58413662; COSMIC: COSV57056720; COSMIC: COSV57056720;