7-95592889-T-C

Position:

• chr7-95592889-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_002612.4(PDK4):​c.400A>G​(p.Met134Val) variant causes a missense change. The variant allele was found at a frequency of 0.00508 in 1,612,224 control chromosomes in the GnomAD database, including 88 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0049 (13 hom., cov: 32)
  • Exomes 𝑓: 0.0051 (75 hom.)
• Consequence: PDK4 NM_002612.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 6.22

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

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.015191466).
• BP6: Variant 7-95592889-T-C is Benign according to our data. Variant chr7-95592889-T-C is described in ClinVar as [Benign]. Clinvar id is 715405.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.00509 (7437/1459948) while in subpopulation MID AF= 0.0397 (229/5762). AF 95% confidence interval is 0.0355. There are 75 homozygotes in gnomad4_exome. There are 4063 alleles in male gnomad4_exome subpopulation. Median coverage is 29. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 13 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PDK4	NM_002612.4	c.400A>G	p.Met134Val	missense_variant	4/11	ENST00000005178.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PDK4	ENST00000005178.6	c.400A>G	p.Met134Val	missense_variant	4/11	1	NM_002612.4	P1
PDK4-AS1	ENST00000665332.1	n.37-20162T>C		intron_variant, non_coding_transcript_variant
PDK4-AS1	ENST00000667350.1	n.90-14051T>C		intron_variant, non_coding_transcript_variant
PDK4-AS1	ENST00000669019.1	n.63-17655T>C		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.00492 AC: 749 AN: 152158 Hom.: 13 Cov.: 32

Gnomad AFR AF: 0.000844

Gnomad AMI AF: 0.00768

Gnomad AMR AF: 0.00883

Gnomad ASJ AF: 0.0450

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.0161

Gnomad FIN AF: 0.000753

Gnomad MID AF: 0.0318

Gnomad NFE AF: 0.00438

Gnomad OTH AF: 0.0100

GnomAD3 exomes AF: 0.00668 AC: 1676 AN: 250810 Hom.: 17 AF XY: 0.00774 AC XY: 1049 AN XY: 135544

Gnomad AFR exome AF: 0.000739

Gnomad AMR exome AF: 0.00400

Gnomad ASJ exome AF: 0.0432

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.0158

Gnomad FIN exome AF: 0.000603

Gnomad NFE exome AF: 0.00473

Gnomad OTH exome AF: 0.00980

GnomAD4 exome AF: 0.00509 AC: 7437 AN: 1459948 Hom.: 75 Cov.: 29 AF XY: 0.00559 AC XY: 4063 AN XY: 726360

Gnomad4 AFR exome AF: 0.00153

Gnomad4 AMR exome AF: 0.00468

Gnomad4 ASJ exome AF: 0.0445

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0158

Gnomad4 FIN exome AF: 0.000375

Gnomad4 NFE exome AF: 0.00353

Gnomad4 OTH exome AF: 0.00812

GnomAD4 genome AF: 0.00491 AC: 748 AN: 152276 Hom.: 13 Cov.: 32 AF XY: 0.00500 AC XY: 372 AN XY: 74448

Gnomad4 AFR AF: 0.000842

Gnomad4 AMR AF: 0.00882

Gnomad4 ASJ AF: 0.0450

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.0161

Gnomad4 FIN AF: 0.000753

Gnomad4 NFE AF: 0.00438

Gnomad4 OTH AF: 0.00993

Alfa AF: 0.00777 Hom.: 18

Bravo AF: 0.00504

TwinsUK AF: 0.00458 AC: 17

ALSPAC AF: 0.00623 AC: 24

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.00477 AC: 41

ExAC AF: 0.00666 AC: 808

Asia WGS AF: 0.00722 AC: 25 AN: 3478

EpiCase AF: 0.00809

EpiControl AF: 0.00688

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Apr 02, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Uncertain	-0.070
CADD	Pathogenic	26
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.49	T
Eigen	Uncertain	0.52
Eigen_PC	Uncertain	0.56
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.96	D
MetaRNN	Benign	0.015	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Uncertain	2.1	M
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.50	T
PROVEAN	Uncertain	-3.6	D
REVEL	Benign	0.25
Sift	Benign	0.076	T
Sift4G	Benign	0.14	T
Polyphen		0.56	P
Vest4		0.84
MVP		0.47
MPC		0.48
ClinPred		0.040	T
GERP RS		5.5
Varity_R		0.73
gMVP		0.83

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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

Other links and lift over

dbSNP: rs144262262; hg19: chr7-95222201;