16-69330536-G-C

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_022341.2(PDF):c.35C>G(p.Pro12Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000156 in 1,478,410 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 (★).

Frequency

Genomes: 𝑓 0.000092 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00016 ( 0 hom. )

Consequence

PDF
NM_022341.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -1.29

Publications

0 publications found

Variant links:

Genes affected

PDF (HGNC:30012): (peptide deformylase, mitochondrial) Protein synthesis proceeds after formylation of methionine by methionyl-tRNA formyl transferase (FMT) and transfer of the charged initiator f-met tRNA to the ribosome. In eubacteria and eukaryotic organelles the product of this gene, peptide deformylase (PDF), removes the formyl group from the initiating methionine of nascent peptides. In eubacteria, deformylation of nascent peptides is required for subsequent cleavage of initiating methionines by methionine aminopeptidase. The discovery that a natural inhibitor of PDF, actinonin, acts as an antimicrobial agent in some bacteria has spurred intensive research into the design of bacterial-specific PDF inhibitors. In human cells, only mitochondrial proteins have N-formylation of initiating methionines. Protein inhibitors of PDF or siRNAs of PDF block the growth of cancer cell lines but have no effect on normal cell growth. In humans, PDF function may therefore be restricted to rapidly growing cells. [provided by RefSeq, Nov 2008]

PDF links:

COG8 (HGNC:18623): (component of oligomeric golgi complex 8) This gene encodes a protein that is a component of the conserved oligomeric Golgi (COG) complex, a multiprotein complex that plays a structural role in the Golgi apparatus, and is involved in intracellular membrane trafficking and glycoprotein modification. Mutations in this gene cause congenital disorder of glycosylation, type IIh, a disease that is characterized by under-glycosylated serum proteins, and whose symptoms include severe psychomotor retardation, failure to thrive, seizures, and dairy and wheat product intolerance. [provided by RefSeq, Jul 2008]

COG8 Gene-Disease associations (from GenCC):

COG8-congenital disorder of glycosylation
Inheritance: AR Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Ambry Genetics, PanelApp Australia, Orphanet, Labcorp Genetics (formerly Invitae)

COG8 links:

ENSG00000272617 (HGNC:):

ENSG00000272617 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -4 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.024188906).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PDF	NM_022341.2 link	c.35C>G	p.Pro12Arg	missense_variant	Exon 1 of 2	ENST00000288022.2	NP_071736.1	Q9HBH1A0A024R6Y3
COG8	NM_032382.5 link	c.*26+277C>G		intron_variant	Intron 5 of 5	ENST00000306875.10	NP_115758.3	Q96MW5A0A024R6Z6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
PDF	ENST00000288022.2 link	c.35C>G	p.Pro12Arg	missense_variant	Exon 1 of 2	1	NM_022341.2	ENSP00000288022.1	Q9HBH1
COG8	ENST00000306875.10 link	c.*26+277C>G		intron_variant	Intron 5 of 5	1	NM_032382.5	ENSP00000305459.6	Q96MW5B4DYU2
ENSG00000272617	ENST00000562949.1 link	c.352-1357C>G		intron_variant	Intron 1 of 1	3		ENSP00000457718.1	H3BUN2
COG8	ENST00000562595.5 link	c.548+4790C>G		intron_variant	Intron 3 of 3	5		ENSP00000456705.1	H3BSH5

Frequencies

GnomAD3 genomes

AF:

0.0000921

AC:

AN:

152042

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000966

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

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:

0.000132

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000775

AC:

AN:

77394

AF XY:

0.0000894

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000176

Gnomad OTH exome

AF:

0.000436

GnomAD4 exome

AF:

0.000163

AC:

216

AN:

1326368

Hom.:

Cov.:

AF XY:

0.000174

AC XY:

114

AN XY:

654510

show subpopulations

African (AFR)

AF:

0.0000757

AC:

AN:

26406

American (AMR)

AF:

0.00

AC:

AN:

26698

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

23176

East Asian (EAS)

AF:

0.00

AC:

AN:

29596

South Asian (SAS)

AF:

0.00

AC:

AN:

73050

European-Finnish (FIN)

AF:

0.00

AC:

AN:

32898

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3924

European-Non Finnish (NFE)

AF:

0.000199

AC:

210

AN:

1055590

Other (OTH)

AF:

0.0000727

AC:

AN:

55030

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.486

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000921

AC:

AN:

152042

Hom.:

Cov.:

AF XY:

0.0000808

AC XY:

AN XY:

74266

show subpopulations

African (AFR)

AF:

0.0000966

AC:

AN:

41426

American (AMR)

AF:

0.0000655

AC:

AN:

15266

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5180

South Asian (SAS)

AF:

0.00

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10594

Middle Eastern (MID)

AF:

0.00

AC:

AN:

314

European-Non Finnish (NFE)

AF:

0.000132

AC:

AN:

67974

Other (OTH)

AF:

0.00

AC:

AN:

2086

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.493

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000680

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Dec 16, 2022

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.35C>G (p.P12R) alteration is located in exon 1 (coding exon 1) of the PDF gene. This alteration results from a C to G substitution at nucleotide position 35, causing the proline (P) at amino acid position 12 to be replaced by an arginine (R). 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

Benign

0.097

BayesDel_addAF

Benign

-0.46

BayesDel_noAF

Benign

-0.63

CADD

Benign

0.024

(source)

DANN

Benign

0.41

DEOGEN2

Benign

0.0037

Eigen

Benign

-2.0

Eigen_PC

Benign

-2.1

FATHMM_MKL

Benign

0.0082

LIST_S2

Benign

0.30

M_CAP

Benign

0.013

MetaRNN

Benign

0.024

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-0.34

PhyloP100

-1.3

PrimateAI

Uncertain

0.71

PROVEAN

Benign

-0.070

REVEL

Benign

0.013

Sift

Benign

0.44

Sift4G

Benign

0.94

Polyphen

0.0

Vest4

0.16

MutPred

0.51

Gain of helix (P = 0.0082);

MVP

0.44

MPC

0.40

ClinPred

0.046

GERP RS

-7.0

PromoterAI

0.073

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.030

gMVP

0.41

Mutation Taster

=99/1

polymorphism

(source)

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over