3-58427681-A-G

Position:

• chr3-58427681-A-G

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.*353T>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 0.298 in 401,114 control chromosomes in the GnomAD database, including 20,220 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.28 (6876 hom., cov: 32)
  • Exomes 𝑓: 0.31 (13344 hom.)
• Consequence: PDHB NM_000925.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.30

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=-0.69).
• BP6: Variant 3-58427681-A-G is Benign according to our data. Variant chr3-58427681-A-G is described in ClinVar as [Benign]. Clinvar id is 346398.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.*353T>C		3_prime_UTR_variant	10/10	ENST00000302746.11	NP_000916.2
PDHB	NM_001315536.2	c.*353T>C		3_prime_UTR_variant	9/9		NP_001302465.1
PDHB	NM_001173468.2	c.*353T>C		3_prime_UTR_variant	11/11		NP_001166939.1
PDHB	NR_033384.2	n.1539T>C		non_coding_transcript_exon_variant	9/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PDHB	ENST00000302746	c.*353T>C		3_prime_UTR_variant	10/10	1	NM_000925.4	ENSP00000307241.6

Frequencies

GnomAD3 genomes AF: 0.278 AC: 42225 AN: 151940 Hom.: 6874 Cov.: 32

Gnomad AFR AF: 0.157

Gnomad AMI AF: 0.313

Gnomad AMR AF: 0.304

Gnomad ASJ AF: 0.500

Gnomad EAS AF: 0.00231

Gnomad SAS AF: 0.203

Gnomad FIN AF: 0.235

Gnomad MID AF: 0.385

Gnomad NFE AF: 0.365

Gnomad OTH AF: 0.328

GnomAD3 exomes AF: 0.286 AC: 26415 AN: 92380 Hom.: 4593 AF XY: 0.287 AC XY: 14451 AN XY: 50314

Gnomad AFR exome AF: 0.150

Gnomad AMR exome AF: 0.273

Gnomad ASJ exome AF: 0.493

Gnomad EAS exome AF: 0.00103

Gnomad SAS exome AF: 0.220

Gnomad FIN exome AF: 0.222

Gnomad NFE exome AF: 0.373

Gnomad OTH exome AF: 0.339

GnomAD4 exome AF: 0.310 AC: 77142 AN: 249056 Hom.: 13344 Cov.: 0 AF XY: 0.305 AC XY: 42807 AN XY: 140312

Gnomad4 AFR exome AF: 0.153

Gnomad4 AMR exome AF: 0.272

Gnomad4 ASJ exome AF: 0.497

Gnomad4 EAS exome AF: 0.00103

Gnomad4 SAS exome AF: 0.233

Gnomad4 FIN exome AF: 0.232

Gnomad4 NFE exome AF: 0.364

Gnomad4 OTH exome AF: 0.316

GnomAD4 genome AF: 0.278 AC: 42232 AN: 152058 Hom.: 6876 Cov.: 32 AF XY: 0.268 AC XY: 19891 AN XY: 74304

Gnomad4 AFR AF: 0.157

Gnomad4 AMR AF: 0.303

Gnomad4 ASJ AF: 0.500

Gnomad4 EAS AF: 0.00251

Gnomad4 SAS AF: 0.204

Gnomad4 FIN AF: 0.235

Gnomad4 NFE AF: 0.365

Gnomad4 OTH AF: 0.324

Alfa AF: 0.334 Hom.: 1739

Bravo AF: 0.278

Asia WGS AF: 0.0940 AC: 332 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	-0.69
CADD	Benign	13
DANN	Benign	0.85

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: rs1126735; hg19: chr3-58413408;