NM_018714.3:c.903G>C

Variant names:

• chr17-73197386-G-C
• rs117208167
• NM_018714.3:c.903G>C

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_018714.3(COG1):​c.903G>C​(p.Gln301His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00815 in 1,614,104 control chromosomes in the GnomAD database, including 67 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0052 (2 hom., cov: 33)
  • Exomes 𝑓: 0.0085 (65 hom.)
• Consequence: COG1 NM_018714.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:8
• Conservation: PhyloP100: 1.25
• Publications: 12 publications found

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 Gene-Disease associations (from GenCC):

• COG1-congenital disorder of glycosylation

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, G2P, PanelApp Australia, ClinGen

ACMG classification

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.003544867).
• BP6: Variant 17-73197386-G-C is Benign according to our data. Variant chr17-73197386-G-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 95920.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00517 (787/152316) while in subpopulation NFE AF = 0.00764 (520/68038). AF 95% confidence interval is 0.0071. There are 2 homozygotes in GnomAd4. There are 359 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 2 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_018714.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COG1	NM_018714.3	MANE Select	c.903G>C	p.Gln301His	missense	Exon 4 of 14	NP_061184.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COG1	ENST00000299886.9	TSL:1 MANE Select	c.903G>C	p.Gln301His	missense	Exon 4 of 14	ENSP00000299886.4
	COG1	ENST00000438720.7	TSL:1	c.900G>C	p.Gln300His	missense	Exon 4 of 13	ENSP00000400111.3
	COG1	ENST00000923183.1		c.897G>C	p.Gln299His	missense	Exon 4 of 14	ENSP00000593242.1

Frequencies

GnomAD3 genomes AF: 0.00518 AC: 788 AN: 152198 Hom.: 2 Cov.: 33

Gnomad AFR AF: 0.00140

Gnomad AMI AF: 0.00439

Gnomad AMR AF: 0.00183

Gnomad ASJ AF: 0.0199

Gnomad EAS AF: 0.000386

Gnomad SAS AF: 0.00228

Gnomad FIN AF: 0.00800

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00764

Gnomad OTH AF: 0.00526

GnomAD2 exomes AF: 0.00559 AC: 1405 AN: 251376 AF XY: 0.00576

Gnomad AFR exome AF: 0.00142

Gnomad AMR exome AF: 0.00130

Gnomad ASJ exome AF: 0.0177

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00686

Gnomad NFE exome AF: 0.00781

Gnomad OTH exome AF: 0.00440

GnomAD4 exome AF: 0.00846 AC: 12365 AN: 1461788 Hom.: 65 Cov.: 35 AF XY: 0.00829 AC XY: 6029 AN XY: 727206

African (AFR) AF: 0.00155 AC: 52 AN: 33480

American (AMR) AF: 0.00154 AC: 69 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0192 AC: 502 AN: 26136

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39700

South Asian (SAS) AF: 0.00335 AC: 289 AN: 86258

European-Finnish (FIN) AF: 0.00714 AC: 381 AN: 53332

Middle Eastern (MID) AF: 0.000520 AC: 3 AN: 5768

European-Non Finnish (NFE) AF: 0.00957 AC: 10643 AN: 1111996

Other (OTH) AF: 0.00702 AC: 424 AN: 60394

GnomAD4 genome AF: 0.00517 AC: 787 AN: 152316 Hom.: 2 Cov.: 33 AF XY: 0.00482 AC XY: 359 AN XY: 74482

African (AFR) AF: 0.00140 AC: 58 AN: 41566

American (AMR) AF: 0.00183 AC: 28 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.0199 AC: 69 AN: 3472

East Asian (EAS) AF: 0.000386 AC: 2 AN: 5176

South Asian (SAS) AF: 0.00207 AC: 10 AN: 4828

European-Finnish (FIN) AF: 0.00800 AC: 85 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00764 AC: 520 AN: 68038

Other (OTH) AF: 0.00520 AC: 11 AN: 2114

Alfa AF: 0.00566 Hom.: 3

Bravo AF: 0.00456

TwinsUK AF: 0.00944 AC: 35

ALSPAC AF: 0.0101 AC: 39

ESP6500AA AF: 0.00136 AC: 6

ESP6500EA AF: 0.00826 AC: 71

ExAC AF: 0.00529 AC: 642

Asia WGS AF: 0.00144 AC: 5 AN: 3478

EpiCase AF: 0.00752

EpiControl AF: 0.00765

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	1	1	COG1 congenital disorder of glycosylation (2)
-	-	2	not specified (2)
-	-	1	COG1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.51	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	22
DANN	Benign	0.92
DEOGEN2	Benign	0.031	T
Eigen	Uncertain	0.20
Eigen_PC	Benign	0.13
FATHMM_MKL	Uncertain	0.76	D
LIST_S2	Benign	0.72	T
M_CAP	Benign	0.0066	T
MetaRNN	Benign	0.0035	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.6	M
PhyloP100		1.2
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-2.1	N
REVEL	Benign	0.076
Sift	Benign	0.037	D
Sift4G	Benign	0.096	T
Polyphen		0.96	D
Vest4		0.16
MutPred		0.20		Gain of methylation at K306 (P = 0.1636)
MVP		0.36
MPC		0.098
ClinPred		0.011	T
GERP RS		3.3
Varity_R		0.067
Mutation Taster		=99/1	polymorphism

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

Other links and lift over

dbSNP: rs117208167; hg19: chr17-71193525; COSMIC: COSV100245394; COSMIC: COSV100245394;