chr16-69330428-T-C

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2PP3

The NM_022341.2(PDF):c.143A>G(p.Tyr48Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000129 in 1,475,926 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000013 ( 0 hom. )

Consequence

PDF
NM_022341.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.55

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: Uncertain_significance. The variant received 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.759

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PDF	NM_022341.2 link	c.143A>G	p.Tyr48Cys	missense_variant	Exon 1 of 2	ENST00000288022.2	NP_071736.1	Q9HBH1A0A024R6Y3
COG8	NM_032382.5 link	c.*26+385A>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.143A>G	p.Tyr48Cys	missense_variant	Exon 1 of 2	1	NM_022341.2	ENSP00000288022.1	Q9HBH1
COG8	ENST00000306875.10 link	c.*26+385A>G		intron_variant	Intron 5 of 5	1	NM_032382.5	ENSP00000305459.6	Q96MW5B4DYU2
ENSG00000272617	ENST00000562949.1 link	c.352-1249A>G		intron_variant	Intron 1 of 1	3		ENSP00000457718.1	H3BUN2
COG8	ENST00000562595.5 link	c.548+4898A>G		intron_variant	Intron 3 of 3	5		ENSP00000456705.1	H3BSH5

Frequencies

GnomAD3 genomes

AF:

0.0000132

AC:

AN:

151832

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000255

AC:

AN:

78442

AF XY:

0.0000221

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000132

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000128

AC:

AN:

1324094

Hom.:

Cov.:

AF XY:

0.0000107

AC XY:

AN XY:

653124

show subpopulations

African (AFR)

AF:

0.0000375

AC:

AN:

26692

American (AMR)

AF:

0.0000750

AC:

AN:

26680

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

23344

East Asian (EAS)

AF:

0.0000350

AC:

AN:

28604

South Asian (SAS)

AF:

0.0000136

AC:

AN:

73438

European-Finnish (FIN)

AF:

0.00

AC:

AN:

32890

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3910

European-Non Finnish (NFE)

AF:

0.0000114

AC:

AN:

1053616

Other (OTH)

AF:

0.00

AC:

AN:

54920

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.487

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome 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

GnomAD4 genome

AF:

0.0000132

AC:

AN:

151832

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74158

show subpopulations

African (AFR)

AF:

0.0000483

AC:

AN:

41396

American (AMR)

AF:

0.00

AC:

AN:

15244

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3464

East Asian (EAS)

AF:

0.00

AC:

AN:

5166

South Asian (SAS)

AF:

0.00

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10510

Middle Eastern (MID)

AF:

0.00

AC:

AN:

314

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67908

Other (OTH)

AF:

0.00

AC:

AN:

2086

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.600

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:

0.0000453

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jan 02, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.143A>G (p.Y48C) alteration is located in exon 1 (coding exon 1) of the PDF gene. This alteration results from a A to G substitution at nucleotide position 143, causing the tyrosine (Y) at amino acid position 48 to be replaced by a cysteine (C). 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

0.26

BayesDel_addAF

Benign

-0.11

BayesDel_noAF

Benign

-0.15

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.041

Eigen

Benign

0.17

Eigen_PC

Benign

0.093

FATHMM_MKL

Benign

0.48

LIST_S2

Benign

0.62

M_CAP

Pathogenic

0.91

MetaRNN

Pathogenic

0.76

MetaSVM

Benign

-0.82

MutationAssessor

Benign

0.90

PhyloP100

1.6

PrimateAI

Pathogenic

0.91

PROVEAN

Benign

-2.3

REVEL

Benign

0.24

Sift

Uncertain

0.0040

Sift4G

Uncertain

0.013

Polyphen

1.0

Vest4

0.46

MutPred

0.44

Gain of catalytic residue at W49 (P = 0.0025);

MVP

0.85

MPC

1.3

ClinPred

0.26

GERP RS

2.8

PromoterAI

-0.046

Neutral

(source)

Varity_R

0.24

gMVP

0.61

Mutation Taster

=56/44

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