3-58430798-C-T

Variant names:

• chr3-58430798-C-T
• NM_000925.4:c.448G>A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_000925.4(PDHB):​c.448G>A​(p.Ala150Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,461,834 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: PDHB NM_000925.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.54

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 Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PDHB	NM_000925.4	c.448G>A	p.Ala150Thr	missense_variant	Exon 6 of 10	ENST00000302746.11	NP_000916.2
PDHB	NM_001315536.2	c.394G>A	p.Ala132Thr	missense_variant	Exon 5 of 9		NP_001302465.1
PDHB	NM_001173468.2	c.404-10G>A		intron_variant	Intron 6 of 10		NP_001166939.1
PDHB	NR_033384.2	n.554G>A		non_coding_transcript_exon_variant	Exon 5 of 9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PDHB	ENST00000302746.11	c.448G>A	p.Ala150Thr	missense_variant	Exon 6 of 10	1	NM_000925.4	ENSP00000307241.6

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461834 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 727222

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.34
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Uncertain	0.060
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.68	D;.;T
Eigen	Uncertain	0.30
Eigen_PC	Uncertain	0.35
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.94	D;D;D
M_CAP	Uncertain	0.14	D
MetaRNN	Uncertain	0.45	T;T;T
MetaSVM	Uncertain	0.73	D
MutationAssessor	Uncertain	2.7	M;.;.
PrimateAI	Uncertain	0.74	T
PROVEAN	Uncertain	-2.6	D;D;D
REVEL	Pathogenic	0.67
Sift	Benign	0.056	T;D;D
Sift4G	Uncertain	0.036	D;D;D
Polyphen		0.41	B;B;B
Vest4		0.45
MutPred		0.66		Loss of glycosylation at S151 (P = 0.196);.;.;
MVP		0.90
MPC		0.45
ClinPred		0.97	D
GERP RS		4.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.61
gMVP		0.94

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr3-58416525;