3-58427738-G-C

Variant names:

• chr3-58427738-G-C
• rs7231
• NM_000925.4:c.*296C>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.*296C>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 0.764 in 499,658 control chromosomes in the GnomAD database, including 146,715 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.73 (41496 hom., cov: 33)
  • Exomes 𝑓: 0.78 (105219 hom.)
• Consequence: PDHB NM_000925.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.110

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=-0.85).
• BP6: Variant 3-58427738-G-C is Benign according to our data. Variant chr3-58427738-G-C is described in ClinVar as [Benign]. Clinvar id is 346399.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.793 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PDHB	NM_000925.4	c.*296C>G		3_prime_UTR_variant	Exon 10 of 10	ENST00000302746.11	NP_000916.2
PDHB	NM_001315536.2	c.*296C>G		3_prime_UTR_variant	Exon 9 of 9		NP_001302465.1
PDHB	NM_001173468.2	c.*296C>G		3_prime_UTR_variant	Exon 11 of 11		NP_001166939.1
PDHB	NR_033384.2	n.1482C>G		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.*296C>G		3_prime_UTR_variant	Exon 10 of 10	1	NM_000925.4	ENSP00000307241.6

Frequencies

GnomAD3 genomes AF: 0.734 AC: 111556 AN: 151922 Hom.: 41483 Cov.: 33

Gnomad AFR AF: 0.611

Gnomad AMI AF: 0.891

Gnomad AMR AF: 0.754

Gnomad ASJ AF: 0.820

Gnomad EAS AF: 0.813

Gnomad SAS AF: 0.812

Gnomad FIN AF: 0.723

Gnomad MID AF: 0.788

Gnomad NFE AF: 0.787

Gnomad OTH AF: 0.767

GnomAD3 exomes AF: 0.771 AC: 99932 AN: 129660 Hom.: 38774 AF XY: 0.777 AC XY: 54958 AN XY: 70688

Gnomad AFR exome AF: 0.599

Gnomad AMR exome AF: 0.715

Gnomad ASJ exome AF: 0.821

Gnomad EAS exome AF: 0.828

Gnomad SAS exome AF: 0.794

Gnomad FIN exome AF: 0.732

Gnomad NFE exome AF: 0.791

Gnomad OTH exome AF: 0.783

GnomAD4 exome AF: 0.776 AC: 269879 AN: 347618 Hom.: 105219 Cov.: 0 AF XY: 0.781 AC XY: 152156 AN XY: 194902

Gnomad4 AFR exome AF: 0.602

Gnomad4 AMR exome AF: 0.717

Gnomad4 ASJ exome AF: 0.817

Gnomad4 EAS exome AF: 0.811

Gnomad4 SAS exome AF: 0.792

Gnomad4 FIN exome AF: 0.730

Gnomad4 NFE exome AF: 0.789

Gnomad4 OTH exome AF: 0.772

GnomAD4 genome AF: 0.734 AC: 111616 AN: 152040 Hom.: 41496 Cov.: 33 AF XY: 0.735 AC XY: 54590 AN XY: 74286

Gnomad4 AFR AF: 0.611

Gnomad4 AMR AF: 0.753

Gnomad4 ASJ AF: 0.820

Gnomad4 EAS AF: 0.813

Gnomad4 SAS AF: 0.811

Gnomad4 FIN AF: 0.723

Gnomad4 NFE AF: 0.787

Gnomad4 OTH AF: 0.768

Alfa AF: 0.761 Hom.: 8131

Bravo AF: 0.727

Asia WGS AF: 0.784 AC: 2726 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 14, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Pyruvate dehydrogenase E1-beta deficiency Benign:1

Jan 13, 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	-0.85
CADD	Benign	4.5
DANN	Benign	0.55
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs7231; hg19: chr3-58413465;