7-95587431-C-T

Variant names:

• chr7-95587431-C-T
• rs1179459338
• NM_002612.4:c.968G>A

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_002612.4(PDK4):​c.968G>A​(p.Arg323Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000941 in 1,594,126 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R323L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000090 (0 hom.)
• Consequence: PDK4 NM_002612.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.31
• Publications: 0 publications found

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)

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3001095).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002612.4. 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
	PDK4	NM_002612.4	MANE Select	c.968G>A	p.Arg323Gln	missense	Exon 9 of 11	NP_002603.1	A4D1H4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PDK4	ENST00000005178.6	TSL:1 MANE Select	c.968G>A	p.Arg323Gln	missense	Exon 9 of 11	ENSP00000005178.5	Q16654
	PDK4	ENST00000886049.1		c.968G>A	p.Arg323Gln	missense	Exon 10 of 12	ENSP00000556108.1
	PDK4	ENST00000886050.1		c.962G>A	p.Arg321Gln	missense	Exon 9 of 11	ENSP00000556109.1

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152098 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000159 AC: 4 AN: 251254 AF XY: 0.0000147

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000217

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000902 AC: 13 AN: 1442028 Hom.: 0 Cov.: 28 AF XY: 0.0000111 AC XY: 8 AN XY: 718800

African (AFR) AF: 0.0000302 AC: 1 AN: 33072

American (AMR) AF: 0.00 AC: 0 AN: 44692

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26014

East Asian (EAS) AF: 0.000101 AC: 4 AN: 39578

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 85850

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53414

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5730

European-Non Finnish (NFE) AF: 0.00000640 AC: 7 AN: 1093922

Other (OTH) AF: 0.00 AC: 0 AN: 59756

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152098 Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1 AN XY: 74310

African (AFR) AF: 0.0000241 AC: 1 AN: 41408

American (AMR) AF: 0.00 AC: 0 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5202

South Asian (SAS) AF: 0.00 AC: 0 AN: 4812

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10600

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68014

Other (OTH) AF: 0.00 AC: 0 AN: 2084

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000302

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.48
CADD	Uncertain	24
DANN	Uncertain	0.98
DEOGEN2	Benign	0.12	T
Eigen	Benign	-0.11
Eigen_PC	Benign	0.084
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Uncertain	0.93	D
M_CAP	Benign	0.015	T
MetaRNN	Benign	0.30	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.2	L
PhyloP100		3.3
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-0.79	N
REVEL	Benign	0.11
Sift	Benign	0.43	T
Sift4G	Benign	0.66	T
Polyphen		0.064	B
Vest4		0.59
MutPred		0.33		Loss of methylation at R323 (P = 0.0516)
MVP		0.58
MPC		0.33
ClinPred		0.42	T
GERP RS		5.8
Varity_R		0.20
gMVP		0.55
Mutation Taster		=85/15	polymorphism

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: rs1179459338; hg19: chr7-95216743;