3-58430811-T-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_000925.4(PDHB):c.435A>G(p.Arg145Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.997 in 1,614,196 control chromosomes in the GnomAD database, including 802,407 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.98 ( 73904 hom., cov: 32)

Exomes 𝑓: 1.0 ( 728503 hom. )

Consequence

PDHB
NM_000925.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: -0.293

Publications

19 publications found

Variant links:

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 Gene-Disease associations (from GenCC):

pyruvate dehydrogenase E1-beta deficiency
Inheritance: AR Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Orphanet, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Ambry Genetics
Leigh syndrome
Inheritance: AR Classification: MODERATE Submitted by: ClinGen

PDHB links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.58).

BP6

Variant 3-58430811-T-C is Benign according to our data. Variant chr3-58430811-T-C is described in ClinVar as Benign. ClinVar VariationId is 559256.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.293 with no splicing effect.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.993 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PDHB	NM_000925.4 link	c.435A>G	p.Arg145Arg	synonymous_variant	Exon 6 of 10	ENST00000302746.11	NP_000916.2	P11177-1A0A384MDR8
PDHB	NM_001315536.2 link	c.381A>G	p.Arg127Arg	synonymous_variant	Exon 5 of 9		NP_001302465.1	P11177-2
PDHB	NR_033384.2 link	n.541A>G		non_coding_transcript_exon_variant	Exon 5 of 9
PDHB	NM_001173468.2 link	c.404-23A>G		intron_variant	Intron 6 of 10		NP_001166939.1	P11177-3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PDHB	ENST00000302746.11 link	c.435A>G	p.Arg145Arg	synonymous_variant	Exon 6 of 10	1	NM_000925.4	ENSP00000307241.6		P11177-1

Frequencies

GnomAD3 genomes

AF:

0.985

AC:

149894

AN:

152204

Hom.:

73848

Cov.:

show subpopulations

Gnomad AFR

AF:

0.948

Gnomad AMI

AF:

1.00

Gnomad AMR

AF:

0.994

Gnomad ASJ

AF:

1.00

Gnomad EAS

AF:

1.00

Gnomad SAS

AF:

1.00

Gnomad FIN

AF:

1.00

Gnomad MID

AF:

0.991

Gnomad NFE

AF:

0.999

Gnomad OTH

AF:

0.985

GnomAD2 exomes

AF:

0.996

AC:

250445

AN:

251488

AF XY:

0.997

show subpopulations

Gnomad AFR exome

AF:

0.947

Gnomad AMR exome

AF:

0.997

Gnomad ASJ exome

AF:

1.00

Gnomad EAS exome

AF:

1.00

Gnomad FIN exome

AF:

1.00

Gnomad NFE exome

AF:

1.00

Gnomad OTH exome

AF:

0.998

GnomAD4 exome

AF:

0.998

AC:

1459397

AN:

1461874

Hom.:

728503

Cov.:

AF XY:

0.999

AC XY:

726176

AN XY:

727238

show subpopulations

African (AFR)

AF:

0.949

AC:

31777

AN:

33476

American (AMR)

AF:

0.997

AC:

44577

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

1.00

AC:

26136

AN:

26136

East Asian (EAS)

AF:

1.00

AC:

39698

AN:

39700

South Asian (SAS)

AF:

1.00

AC:

86251

AN:

86258

European-Finnish (FIN)

AF:

1.00

AC:

53408

AN:

53418

Middle Eastern (MID)

AF:

0.997

AC:

5749

AN:

5768

European-Non Finnish (NFE)

AF:

1.00

AC:

1111628

AN:

1111998

Other (OTH)

AF:

0.996

AC:

60173

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.476

Heterozygous variant carriers

139

278

418

557

696

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

21670

43340

65010

86680

108350

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.985

AC:

150009

AN:

152322

Hom.:

73904

Cov.:

AF XY:

0.986

AC XY:

73424

AN XY:

74486

show subpopulations

African (AFR)

AF:

0.948

AC:

39400

AN:

41552

American (AMR)

AF:

0.994

AC:

15218

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

1.00

AC:

3472

AN:

3472

East Asian (EAS)

AF:

1.00

AC:

5180

AN:

5180

South Asian (SAS)

AF:

1.00

AC:

4825

AN:

4826

European-Finnish (FIN)

AF:

1.00

AC:

10624

AN:

10624

Middle Eastern (MID)

AF:

0.986

AC:

290

AN:

294

European-Non Finnish (NFE)

AF:

0.999

AC:

68005

AN:

68044

Other (OTH)

AF:

0.985

AC:

2083

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

115

230

344

459

574

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

914

1828

2742

3656

4570

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.992

Hom.:

49854

Bravo

AF:

0.983

Asia WGS

AF:

0.998

AC:

3469

AN:

3478

EpiCase

AF:

1.00

EpiControl

AF:

1.00

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Pyruvate dehydrogenase E1-beta deficiency

Benign:3

Jun 15, 2021

Pars Genome Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Sep 05, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:2

Feb 23, 2016

Mayo Clinic Laboratories, Mayo Clinic

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Pyruvate dehydrogenase phosphatase deficiency

Benign:1

Nov 16, 2019

Natera, Inc.

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.58

CADD

Benign

(source)

DANN

Benign

0.84

PhyloP100

-0.29

Mutation Taster

=93/7

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over