13-45480127-A-G

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_031431.4(COG3):c.386A>G(p.Gln129Arg) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.000000687 in 1,456,050 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. 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. Q129P) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

COG3
NM_031431.4 missense, splice_region

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.82

Publications

0 publications found

Variant links:

Genes affected

COG3 (HGNC:18619): (component of oligomeric golgi complex 3) This gene encodes a component of the conserved oligomeric Golgi (COG) complex which is composed of eight different subunits and is required for normal Golgi morphology and localization. Defects in the COG complex result in multiple deficiencies in protein glycosylation. The protein encoded by this gene is involved in ER-Golgi transport.[provided by RefSeq, Jun 2011]

COG3 Gene-Disease associations (from GenCC):

congenital disorder of glycosylation, type IIbb
Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics

COG3 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.19652441).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COG3	NM_031431.4 link	c.386A>G	p.Gln129Arg	missense_variant, splice_region_variant	Exon 4 of 23	ENST00000349995.10	NP_113619.3	Q96JB2-1
COG3	XM_047430702.1 link	c.386A>G	p.Gln129Arg	missense_variant, splice_region_variant	Exon 4 of 19		XP_047286658.1
COG3	XR_007063702.1 link	n.484A>G		splice_region_variant, non_coding_transcript_exon_variant	Exon 4 of 14
COG3	XR_429222.5 link	n.484A>G		splice_region_variant, non_coding_transcript_exon_variant	Exon 4 of 24

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COG3	ENST00000349995.10 link	c.386A>G	p.Gln129Arg	missense_variant, splice_region_variant	Exon 4 of 23	1	NM_031431.4	ENSP00000258654.8		Q96JB2-1
COG3	ENST00000617493.1 link	c.386A>G	p.Gln129Arg	missense_variant, splice_region_variant	Exon 4 of 12	1		ENSP00000481332.1		Q96JB2-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.87e-7

AC:

AN:

1456050

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

724142

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

33364

American (AMR)

AF:

0.00

AC:

AN:

44286

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25924

East Asian (EAS)

AF:

0.00

AC:

AN:

39622

South Asian (SAS)

AF:

0.00

AC:

AN:

85318

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53170

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5732

European-Non Finnish (NFE)

AF:

9.02e-7

AC:

AN:

1108554

Other (OTH)

AF:

0.00

AC:

AN:

60080

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.325

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Sep 11, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.386A>G (p.Q129R) alteration is located in exon 4 (coding exon 4) of the COG3 gene. This alteration results from a A to G substitution at nucleotide position 386, causing the glutamine (Q) at amino acid position 129 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.085

BayesDel_addAF

Benign

-0.19

BayesDel_noAF

Benign

-0.51

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.028

T;.

Eigen

Benign

-0.21

Eigen_PC

Benign

0.010

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Benign

0.79

T;T

M_CAP

Benign

0.0061

MetaRNN

Benign

0.20

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.83

L;L

PhyloP100

4.8

PrimateAI

Uncertain

0.59

PROVEAN

Benign

-1.3

N;.

REVEL

Benign

0.038

Sift

Benign

0.45

T;.

Sift4G

Benign

0.47

T;T

Polyphen

0.10

B;B

Vest4

0.21

MutPred

0.42

Loss of ubiquitination at K126 (P = 0.071);Loss of ubiquitination at K126 (P = 0.071);

MVP

0.46

MPC

0.29

ClinPred

0.66

GERP RS

4.8

Varity_R

0.18

gMVP

0.26

Mutation Taster

=79/21

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over