rs150001655

Positions:

• chr17-73196720-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_018714.3(COG1):​c.529A>G​(p.Ile177Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000983 in 1,613,850 control chromosomes in the GnomAD database, including 12 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 Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0050 (6 hom., cov: 33)
  • Exomes 𝑓: 0.00056 (6 hom.)
• Consequence: COG1 NM_018714.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 1.70

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.008609146).
• BP6: Variant 17-73196720-A-G is Benign according to our data. Variant chr17-73196720-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 376973.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-73196720-A-G is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00501 (762/152164) while in subpopulation AFR AF= 0.0169 (702/41512). AF 95% confidence interval is 0.0159. There are 6 homozygotes in gnomad4. There are 333 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 6 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COG1	NM_018714.3	c.529A>G	p.Ile177Val	missense_variant	2/14	ENST00000299886.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COG1	ENST00000299886.9	c.529A>G	p.Ile177Val	missense_variant	2/14	1	NM_018714.3	P1
COG1	ENST00000438720.7	c.529A>G	p.Ile177Val	missense_variant	2/13	1
COG1	ENST00000582587.2	c.*153A>G		3_prime_UTR_variant, NMD_transcript_variant	2/3	3

Frequencies

GnomAD3 genomes AF: 0.00499 AC: 759 AN: 152046 Hom.: 6 Cov.: 33

Gnomad AFR AF: 0.0169

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00223

Gnomad ASJ AF: 0.00317

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.00431

GnomAD3 exomes AF: 0.00137 AC: 343 AN: 250278 Hom.: 4 AF XY: 0.000953 AC XY: 129 AN XY: 135422

Gnomad AFR exome AF: 0.0153

Gnomad AMR exome AF: 0.00142

Gnomad ASJ exome AF: 0.00288

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000710

Gnomad OTH exome AF: 0.00131

GnomAD4 exome AF: 0.000564 AC: 824 AN: 1461686 Hom.: 6 Cov.: 63 AF XY: 0.000483 AC XY: 351 AN XY: 727172

Gnomad4 AFR exome AF: 0.0149

Gnomad4 AMR exome AF: 0.00157

Gnomad4 ASJ exome AF: 0.00245

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000464

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000809

Gnomad4 OTH exome AF: 0.00147

GnomAD4 genome AF: 0.00501 AC: 762 AN: 152164 Hom.: 6 Cov.: 33 AF XY: 0.00448 AC XY: 333 AN XY: 74384

Gnomad4 AFR AF: 0.0169

Gnomad4 AMR AF: 0.00222

Gnomad4 ASJ AF: 0.00317

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000735

Gnomad4 OTH AF: 0.00426

Alfa AF: 0.00132 Hom.: 1

Bravo AF: 0.00553

ESP6500AA AF: 0.0125 AC: 55

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.00160 AC: 194

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.000178

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

COG1 congenital disorder of glycosylation Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 07, 2024	- -
Likely benign, 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 and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

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

Sep 02, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.095
BayesDel_addAF	Benign	-0.62	T
BayesDel_noAF	Benign	-0.65
CADD	Benign	9.9
DANN	Benign	0.87
DEOGEN2	Benign	0.0018	T;T
Eigen	Benign	-0.73
Eigen_PC	Benign	-0.50
FATHMM_MKL	Uncertain	0.78	D
LIST_S2	Benign	0.70	T;T
MetaRNN	Benign	0.0086	T;T
MetaSVM	Benign	-0.99	T
MutationTaster	Benign	0.87	N
PrimateAI	Benign	0.30	T
Sift4G	Benign	0.41	T;T
Polyphen		0.0	.;B
Vest4		0.051
MVP		0.23
MPC		0.084
ClinPred		0.0028	T
GERP RS		0.17
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.025

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: rs150001655; hg19: chr17-71192859; COSMIC: COSV100245376; COSMIC: COSV100245376;