chr7-95587513-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3

The NM_002612.4(PDK4):​c.886G>A​(p.Gly296Ser) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)
Exomes 𝑓: 0.0 ( 0 hom. )
Failed GnomAD Quality Control

Consequence

PDK4
NM_002612.4 missense

Scores

4
10
5

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.13
Variant links:
Genes affected
PDK4 (HGNC:8812): (pyruvate dehydrogenase kinase 4) This gene is a member of the PDK/BCKDK protein kinase family and encodes a mitochondrial protein with a histidine kinase domain. This protein is located in the matrix of the mitrochondria and inhibits the pyruvate dehydrogenase complex by phosphorylating one of its subunits, thereby contributing to the regulation of glucose metabolism. Expression of this gene is regulated by glucocorticoids, retinoic acid and insulin. [provided by RefSeq, Jul 2008]
PDK4-AS1 (HGNC:55767): (PDK4 antisense RNA 1)

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.774

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
PDK4NM_002612.4 linkuse as main transcriptc.886G>A p.Gly296Ser missense_variant 9/11 ENST00000005178.6

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
PDK4ENST00000005178.6 linkuse as main transcriptc.886G>A p.Gly296Ser missense_variant 9/111 NM_002612.4 P1
PDK4-AS1ENST00000665332.1 linkuse as main transcriptn.37-25538C>T intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
Data not reliable, filtered out with message: AC0
AF:
0.00
AC:
0
AN:
1443638
Hom.:
0
Cov.:
28
AF XY:
0.00
AC XY:
0
AN XY:
719512
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:
0.00
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
33
Bravo
AF:
0.00000378

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsApr 04, 2024The c.886G>A (p.G296S) alteration is located in exon 9 (coding exon 9) of the PDK4 gene. This alteration results from a G to A substitution at nucleotide position 886, causing the glycine (G) at amino acid position 296 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
0.37
BayesDel_addAF
Uncertain
0.082
D
BayesDel_noAF
Benign
-0.12
CADD
Pathogenic
28
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.57
D
Eigen
Pathogenic
0.79
Eigen_PC
Pathogenic
0.79
FATHMM_MKL
Uncertain
0.96
D
LIST_S2
Uncertain
0.97
D
M_CAP
Benign
0.027
D
MetaRNN
Pathogenic
0.77
D
MetaSVM
Benign
-0.51
T
MutationAssessor
Benign
1.7
L
MutationTaster
Benign
1.0
D
PrimateAI
Uncertain
0.60
T
PROVEAN
Pathogenic
-5.6
D
REVEL
Uncertain
0.38
Sift
Uncertain
0.0080
D
Sift4G
Uncertain
0.027
D
Polyphen
0.99
D
Vest4
0.57
MutPred
0.64
Gain of glycosylation at G296 (P = 0.0194);
MVP
0.87
MPC
0.49
ClinPred
1.0
D
GERP RS
5.6
Varity_R
0.82
gMVP
0.92

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs1791500558; hg19: chr7-95216825; API