3-58430811-T-C

Variant names:

• chr3-58430811-T-C
• rs4264746
• NM_000925.4:c.435A>G

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.293
• Publications: 19 publications found

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: Labcorp Genetics (formerly Invitae), Orphanet, Genomics England PanelApp, Ambry Genetics
• Leigh syndrome

  Inheritance: AR Classification: MODERATE Submitted by: ClinGen

ACMG classification

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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000925.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PDHB	NM_000925.4	MANE Select	c.435A>G	p.Arg145Arg	synonymous	Exon 6 of 10	NP_000916.2	A0A384MDR8
	PDHB	NM_001315536.2		c.381A>G	p.Arg127Arg	synonymous	Exon 5 of 9	NP_001302465.1	P11177-2
	PDHB	NM_001173468.2		c.404-23A>G		intron	N/A	NP_001166939.1	P11177-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PDHB	ENST00000302746.11	TSL:1 MANE Select	c.435A>G	p.Arg145Arg	synonymous	Exon 6 of 10	ENSP00000307241.6	P11177-1
	PDHB	ENST00000383714.8	TSL:1	c.381A>G	p.Arg127Arg	synonymous	Exon 5 of 9	ENSP00000373220.4	P11177-2
	PDHB	ENST00000461692.5	TSL:1	n.548A>G		non_coding_transcript_exon	Exon 5 of 9

Frequencies

GnomAD3 genomes AF: 0.985 AC: 149894 AN: 152204 Hom.: 73848 Cov.: 32

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

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.: 54 AF XY: 0.999 AC XY: 726176 AN XY: 727238

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

GnomAD4 genome AF: 0.985 AC: 150009 AN: 152322 Hom.: 73904 Cov.: 32 AF XY: 0.986 AC XY: 73424 AN XY: 74486

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

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

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	Pyruvate dehydrogenase E1-beta deficiency (3)
-	-	2	not provided (2)
-	-	1	Pyruvate dehydrogenase phosphatase deficiency (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.58
CADD	Benign	11
DANN	Benign	0.84
PhyloP100		-0.29
Mutation Taster		=93/7	polymorphism (auto)

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

Other links and lift over

dbSNP: rs4264746; hg19: chr3-58416538; COSMIC: COSV108138100; COSMIC: COSV108138100;