16-69328876-C-A

Position:

• chr16-69328876-C-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_032382.5(COG8):​c.*330G>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0689 in 1,047,084 control chromosomes in the GnomAD database, including 2,907 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.060 (346 hom., cov: 33)
  • Exomes 𝑓: 0.070 (2561 hom.)
• Consequence: COG8 NM_032382.5 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.0400

Genes affected

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]

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]

ENSG00000272617 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.72).
• BP6: Variant 16-69328876-C-A is Benign according to our data. Variant chr16-69328876-C-A is described in ClinVar as [Benign]. Clinvar id is 320306.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.14 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COG8	NM_032382.5	c.*330G>T		3_prime_UTR_variant	6/6	ENST00000306875.10	NP_115758.3
PDF	NM_022341.2	c.*146G>T		3_prime_UTR_variant	2/2	ENST00000288022.2	NP_071736.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COG8	ENST00000306875	c.*330G>T		3_prime_UTR_variant	6/6	1	NM_032382.5	ENSP00000305459.6
PDF	ENST00000288022	c.*146G>T		3_prime_UTR_variant	2/2	1	NM_022341.2	ENSP00000288022.1
ENSG00000272617	ENST00000562949	c.*160G>T		3_prime_UTR_variant	2/2	3		ENSP00000457718.1
COG8	ENST00000562595.5	c.549-5173G>T		intron_variant		5		ENSP00000456705.1

Frequencies

GnomAD3 genomes AF: 0.0603 AC: 9173 AN: 152188 Hom.: 343 Cov.: 33

Gnomad AFR AF: 0.0307

Gnomad AMI AF: 0.0859

Gnomad AMR AF: 0.0591

Gnomad ASJ AF: 0.0423

Gnomad EAS AF: 0.0498

Gnomad SAS AF: 0.148

Gnomad FIN AF: 0.0896

Gnomad MID AF: 0.0348

Gnomad NFE AF: 0.0694

Gnomad OTH AF: 0.0556

GnomAD4 exome AF: 0.0703 AC: 62913 AN: 894778 Hom.: 2561 Cov.: 12 AF XY: 0.0731 AC XY: 33229 AN XY: 454406

Gnomad4 AFR exome AF: 0.0299

Gnomad4 AMR exome AF: 0.0424

Gnomad4 ASJ exome AF: 0.0413

Gnomad4 EAS exome AF: 0.0616

Gnomad4 SAS exome AF: 0.145

Gnomad4 FIN exome AF: 0.0908

Gnomad4 NFE exome AF: 0.0669

Gnomad4 OTH exome AF: 0.0644

GnomAD4 genome AF: 0.0604 AC: 9200 AN: 152306 Hom.: 346 Cov.: 33 AF XY: 0.0630 AC XY: 4692 AN XY: 74472

Gnomad4 AFR AF: 0.0310

Gnomad4 AMR AF: 0.0591

Gnomad4 ASJ AF: 0.0423

Gnomad4 EAS AF: 0.0501

Gnomad4 SAS AF: 0.149

Gnomad4 FIN AF: 0.0896

Gnomad4 NFE AF: 0.0694

Gnomad4 OTH AF: 0.0598

Alfa AF: 0.0101 Hom.: 50

Bravo AF: 0.0533

Asia WGS AF: 0.129 AC: 447 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

COG8-congenital disorder of glycosylation Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.72
CADD	Benign	15
DANN	Benign	0.78
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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

LitVar

Other links and lift over

dbSNP: rs1055399; hg19: chr16-69362779; COSMIC: COSV54750666; COSMIC: COSV54750666;