16-69339245-A-T

Position:

• chr16-69339245-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_032382.5(COG8):​c.308T>A​(p.Leu103Gln) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: COG8 NM_032382.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.52

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]

ENSG00000260371 (HGNC:):

NIP7 (HGNC:24328): (nucleolar pre-rRNA processing protein NIP7) Enables RNA binding activity. Predicted to be involved in ribosomal large subunit biogenesis. Located in cytosol; nucleolus; and nucleoplasm. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.15397689).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COG8	NM_032382.5	c.308T>A	p.Leu103Gln	missense_variant	1/6	ENST00000306875.10	NP_115758.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COG8	ENST00000306875.10	c.308T>A	p.Leu103Gln	missense_variant	1/6	1	NM_032382.5	ENSP00000305459.6
ENSG00000260371	ENST00000563634.1	c.3-2533T>A		intron_variant		4		ENSP00000454500.1
ENSG00000259900	ENST00000564737.1	n.466-2533T>A		intron_variant		5		ENSP00000462747.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

COG8-congenital disorder of glycosylation Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 15, 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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.097
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.40
CADD	Benign	23
DANN	Benign	0.91
DEOGEN2	Benign	0.012	.;T;T
Eigen	Benign	-0.37
Eigen_PC	Benign	-0.094
FATHMM_MKL	Benign	0.61	D
LIST_S2	Uncertain	0.91	D;D;D
M_CAP	Benign	0.016	T
MetaRNN	Benign	0.15	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.90	.;N;.
PrimateAI	Uncertain	0.64	T
PROVEAN	Benign	3.2	.;.;N
REVEL	Benign	0.14
Sift	Benign	0.44	.;.;T
Sift4G	Benign	0.35	.;.;T
Polyphen		0.012	B;B;.
Vest4		0.43
MutPred		0.45		.;Loss of catalytic residue at L103 (P = 0.0015);Loss of catalytic residue at L103 (P = 0.0015);
MVP		0.36
MPC		0.87
ClinPred		0.82	D
GERP RS		5.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.27
gMVP		0.41

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: rs2012390315; hg19: chr16-69373148;