16-69330536-G-T

Variant names:

• chr16-69330536-G-T
• rs960880193
• NM_022341.2:c.35C>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_022341.2(PDF):​c.35C>A​(p.Pro12Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000754 in 1,326,368 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P12R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.5e-7 (0 hom.)
• Consequence: PDF NM_022341.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.29
• Publications: 0 publications found

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]

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)

ENSG00000272617 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.03647417).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PDF	NM_022341.2	c.35C>A	p.Pro12Gln	missense_variant	Exon 1 of 2	ENST00000288022.2	NP_071736.1
COG8	NM_032382.5	c.*26+277C>A		intron_variant	Intron 5 of 5	ENST00000306875.10	NP_115758.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PDF	ENST00000288022.2	c.35C>A	p.Pro12Gln	missense_variant	Exon 1 of 2	1	NM_022341.2	ENSP00000288022.1
COG8	ENST00000306875.10	c.*26+277C>A		intron_variant	Intron 5 of 5	1	NM_032382.5	ENSP00000305459.6
ENSG00000272617	ENST00000562949.1	c.352-1357C>A		intron_variant	Intron 1 of 1	3		ENSP00000457718.1
COG8	ENST00000562595.5	c.548+4790C>A		intron_variant	Intron 3 of 3	5		ENSP00000456705.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 7.54e-7 AC: 1 AN: 1326368 Hom.: 0 Cov.: 32 AF XY: 0.00000153 AC XY: 1 AN XY: 654510

African (AFR) AF: 0.00 AC: 0 AN: 26406

American (AMR) AF: 0.0000375 AC: 1 AN: 26698

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23176

East Asian (EAS) AF: 0.00 AC: 0 AN: 29596

South Asian (SAS) AF: 0.00 AC: 0 AN: 73050

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 32898

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3924

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1055590

Other (OTH) AF: 0.00 AC: 0 AN: 55030

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.60
CADD	Benign	0.054
DANN	Benign	0.54
DEOGEN2	Benign	0.0038	T
Eigen	Benign	-1.9
Eigen_PC	Benign	-2.0
FATHMM_MKL	Benign	0.013	N
LIST_S2	Benign	0.29	T
M_CAP	Benign	0.016	T
MetaRNN	Benign	0.036	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.0	N
PhyloP100		-1.3
PrimateAI	Uncertain	0.69	T
PROVEAN	Benign	-0.12	N
REVEL	Benign	0.014
Sift	Benign	0.15	T
Sift4G	Benign	0.40	T
Polyphen		0.0	B
Vest4		0.28
MutPred		0.49		Gain of helix (P = 0.0082);
MVP		0.43
MPC		0.35
ClinPred		0.13	T
GERP RS		-7.0
PromoterAI		-0.11	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.035
gMVP		0.44

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: rs960880193; hg19: chr16-69364439;