3-58427833-A-G

Position:

• chr3-58427833-A-G

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_000925.4(PDHB):​c.*201T>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 0.00065 in 649,086 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00028 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00076 (2 hom.)
• Consequence: PDHB NM_000925.4 3_prime_UTR
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.422

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 3-58427833-A-G is Benign according to our data. Variant chr3-58427833-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 903459.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.000282 (43/152334) while in subpopulation SAS AF= 0.00373 (18/4832). AF 95% confidence interval is 0.00241. There are 0 homozygotes in gnomad4. There are 20 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PDHB	NM_000925.4	c.*201T>C		3_prime_UTR_variant	10/10	ENST00000302746.11	NP_000916.2
PDHB	NM_001315536.2	c.*201T>C		3_prime_UTR_variant	9/9		NP_001302465.1
PDHB	NM_001173468.2	c.*201T>C		3_prime_UTR_variant	11/11		NP_001166939.1
PDHB	NR_033384.2	n.1387T>C		non_coding_transcript_exon_variant	9/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PDHB	ENST00000302746	c.*201T>C		3_prime_UTR_variant	10/10	1	NM_000925.4	ENSP00000307241.6

Frequencies

GnomAD3 genomes AF: 0.000282 AC: 43 AN: 152216 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00372

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000294

Gnomad OTH AF: 0.000955

GnomAD3 exomes AF: 0.000987 AC: 132 AN: 133672 Hom.: 1 AF XY: 0.00131 AC XY: 95 AN XY: 72584

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000818

Gnomad ASJ exome AF: 0.000122

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00447

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000444

Gnomad OTH exome AF: 0.00123

GnomAD4 exome AF: 0.000763 AC: 379 AN: 496752 Hom.: 2 Cov.: 3 AF XY: 0.00102 AC XY: 275 AN XY: 270776

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000905

Gnomad4 ASJ exome AF: 0.0000540

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00358

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000448

Gnomad4 OTH exome AF: 0.000511

GnomAD4 genome AF: 0.000282 AC: 43 AN: 152334 Hom.: 0 Cov.: 32 AF XY: 0.000268 AC XY: 20 AN XY: 74500

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00373

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000294

Gnomad4 OTH AF: 0.000945

Alfa AF: 0.000684 Hom.: 0

Bravo AF: 0.000276

Asia WGS AF: 0.00260 AC: 9 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Pyruvate dehydrogenase E1-beta deficiency Benign:1

Likely 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	2.8
DANN	Benign	0.66
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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: rs375277648; hg19: chr3-58413560;