rs148773959

chr17-73206754-G-A

Variant summary

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

The NM_018714.3(COG1):c.2666G>A(p.Arg889Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000447 in 1,611,962 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R889W) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000047 ( 1 hom., cov: 27)

Exomes 𝑓: 0.000044 ( 0 hom. )

Consequence

COG1
NM_018714.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:3

Conservation

PhyloP100: 7.51

Variant links:

Genes affected

COG1 (HGNC:6545): (component of oligomeric golgi complex 1) The protein encoded by this gene is one of eight proteins (Cog1-8) which form a Golgi-localized complex (COG) required for normal Golgi morphology and function. It is thought that this protein is required for steps in the normal medial and trans Golgi-associated processing of glycoconjugates and plays a role in the organization of the Golgi-localized complex. [provided by RefSeq, Jul 2008]

COG1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COG1	NM_018714.3 linkuse as main transcript	c.2666G>A	p.Arg889Gln	missense_variant	12/14	ENST00000299886.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COG1	ENST00000299886.9 linkuse as main transcript	c.2666G>A	p.Arg889Gln	missense_variant	12/14	1	NM_018714.3	P1

Frequencies

GnomAD3 genomes

AF:

0.0000466

AC:

AN:

150260

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000492

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:

0.0000590

Gnomad OTH

AF:

0.000486

GnomAD3 exomes

AF:

0.0000358

AC:

AN:

251444

Hom.:

AF XY:

0.0000441

AC XY:

AN XY:

135904

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.0000578

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000528

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000445

AC:

AN:

1461702

Hom.:

Cov.:

AF XY:

0.0000495

AC XY:

AN XY:

727164

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000447

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000549

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000466

AC:

AN:

150260

Hom.:

Cov.:

AF XY:

0.0000410

AC XY:

AN XY:

73192

show subpopulations

Gnomad4 AFR

AF:

0.0000492

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000590

Gnomad4 OTH

AF:

0.000486

Alfa

AF:

0.0000403

Hom.:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000330

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

COG1 congenital disorder of glycosylation

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Nov 27, 2023	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 889 of the COG1 protein (p.Arg889Gln). This variant is present in population databases (rs148773959, gnomAD 0.006%). This variant has not been reported in the literature in individuals affected with COG1-related conditions. ClinVar contains an entry for this variant (Variation ID: 324975). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on COG1 protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Uncertain significance, 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, 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. -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Sep 11, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.14

BayesDel_noAF

Benign

-0.25

Cadd

Pathogenic

Dann

Benign

0.95

DEOGEN2

Benign

0.037

T;T

Eigen

Uncertain

0.50

Eigen_PC

Uncertain

0.42

FATHMM_MKL

Uncertain

0.97

LIST_S2

Uncertain

0.89

D;D

M_CAP

Benign

0.034

MetaRNN

Uncertain

0.61

D;D

MetaSVM

Benign

-0.94

MutationTaster

Benign

1.0

PrimateAI

Benign

0.43

Sift4G

Benign

0.090

T;T

Polyphen

1.0

.;D

Vest4

0.69

MVP

0.37

MPC

0.16

ClinPred

0.42

GERP RS

3.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.15

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over