rs141750466

chr17-73201539-G-A

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_018714.3(COG1):c.1712G>A(p.Arg571Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00289 in 1,614,234 control chromosomes in the GnomAD database, including 40 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R571W) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0037 (10 hom., cov: 33)
  • Exomes 𝑓: 0.0028 (30 hom.)
• Consequence: COG1 NM_018714.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:5
• Conservation: PhyloP100: 1.77

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]

ACMG classification

Verdict is Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0034083128).
• BP6: Variant 17-73201539-G-A is Benign according to our data. Variant chr17-73201539-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 252724.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Benign=3, Likely_benign=2}.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0037 (564/152348) while in subpopulation NFE AF= 0.00517 (352/68040). AF 95% confidence interval is 0.00473. There are 10 homozygotes in gnomad4. There are 314 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 10 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COG1	NM_018714.3	c.1712G>A	p.Arg571Gln	missense_variant	7/14	ENST00000299886.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COG1	ENST00000299886.9	c.1712G>A	p.Arg571Gln	missense_variant	7/14	1	NM_018714.3	P1
COG1	ENST00000438720.7	c.1712G>A	p.Arg571Gln	missense_variant	7/13	1

Frequencies

GnomAD3 genomes AF: 0.00370 AC: 564 AN: 152230 Hom.: 10 Cov.: 33

Gnomad AFR AF: 0.000290

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000524

Gnomad ASJ AF: 0.00230

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0169

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00517

Gnomad OTH AF: 0.00239

GnomAD3 exomes AF: 0.00379 AC: 952 AN: 251366 Hom.: 10 AF XY: 0.00364 AC XY: 495 AN XY: 135876

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.000520

Gnomad ASJ exome AF: 0.00367

Gnomad EAS exome AF: 0.000109

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0170

Gnomad NFE exome AF: 0.00443

Gnomad OTH exome AF: 0.00375

GnomAD4 exome AF: 0.00280 AC: 4094 AN: 1461886 Hom.: 30 Cov.: 63 AF XY: 0.00297 AC XY: 2161 AN XY: 727242

Gnomad4 AFR exome AF: 0.000149

Gnomad4 AMR exome AF: 0.000581

Gnomad4 ASJ exome AF: 0.00429

Gnomad4 EAS exome AF: 0.000101

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.0171

Gnomad4 NFE exome AF: 0.00259

Gnomad4 OTH exome AF: 0.00242

GnomAD4 genome AF: 0.00370 AC: 564 AN: 152348 Hom.: 10 Cov.: 33 AF XY: 0.00422 AC XY: 314 AN XY: 74494

Gnomad4 AFR AF: 0.000289

Gnomad4 AMR AF: 0.000523

Gnomad4 ASJ AF: 0.00230

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0169

Gnomad4 NFE AF: 0.00517

Gnomad4 OTH AF: 0.00236

Alfa AF: 0.00371 Hom.: 2

Bravo AF: 0.00190

TwinsUK AF: 0.00108 AC: 4

ALSPAC AF: 0.00311 AC: 12

ESP6500AA AF: 0.000681 AC: 3

ESP6500EA AF: 0.00442 AC: 38

ExAC AF: 0.00401 AC: 487

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00376

EpiControl AF: 0.00249

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:5

Revision: criteria provided, conflicting classifications

Submissions by phenotype

COG1 congenital disorder of glycosylation Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 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. -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	- -

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Sep 15, 2016	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2024	COG1: BP4, BS2 -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia

Nov 16, 2015

- -

COG1-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 05, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.058
BayesDel_addAF	Benign	-0.61	T
BayesDel_noAF	Benign	-0.64
Cadd	Benign	3.6
Dann	Benign	0.80
DEOGEN2	Benign	0.0016	T;T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.36	N
LIST_S2	Benign	0.83	T;T
MetaRNN	Benign	0.0034	T;T
MetaSVM	Benign	-0.98	T
MutationTaster	Benign	0.84	N
PrimateAI	Benign	0.19	T
Sift4G	Benign	0.50	T;T
Polyphen		0.0050	.;B
Vest4		0.081
MVP		0.25
MPC		0.12
ClinPred		0.0026	T
GERP RS		-3.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.041

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: rs141750466; hg19: chr17-71197678;