13-45465149-G-A

Position:

• chr13-45465149-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PM1 PM2 BP4_Moderate

The NM_031431.4(COG3):​c.113G>A​(p.Arg38Lys) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: COG3 NM_031431.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.72

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 uncertain in NM_031431.4
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.09928167).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COG3	NM_031431.4	c.113G>A	p.Arg38Lys	missense_variant	1/23	ENST00000349995.10
COG3	XM_047430702.1	c.113G>A	p.Arg38Lys	missense_variant	1/19
COG3	XR_007063702.1	n.211G>A		non_coding_transcript_exon_variant	1/14
COG3	XR_429222.5	n.211G>A		non_coding_transcript_exon_variant	1/24

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COG3	ENST00000349995.10	c.113G>A	p.Arg38Lys	missense_variant	1/23	1	NM_031431.4	P1
COG3	ENST00000617493.1	c.113G>A	p.Arg38Lys	missense_variant	1/12	1
COG3	ENST00000476702.1	c.86G>A	p.Arg29Lys	missense_variant	1/2	3
COG3	ENST00000617325.1	n.252G>A		non_coding_transcript_exon_variant	1/2	3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 20, 2024

The c.113G>A (p.R38K) alteration is located in exon 1 (coding exon 1) of the COG3 gene. This alteration results from a G to A substitution at nucleotide position 113, causing the arginine (R) at amino acid position 38 to be replaced by a lysine (K). 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	0.086
BayesDel_addAF	Benign	-0.10	T
BayesDel_noAF	Benign	-0.38
CADD	Benign	20
DANN	Benign	0.97
DEOGEN2	Benign	0.0040	T;.
Eigen	Benign	-0.23
Eigen_PC	Benign	-0.026
FATHMM_MKL	Benign	0.56	D
LIST_S2	Benign	0.79	T;T
M_CAP	Benign	0.036	D
MetaRNN	Benign	0.099	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.4	L;L
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.75	T
PROVEAN	Benign	-0.18	N;.
REVEL	Benign	0.059
Sift	Benign	0.88	T;.
Sift4G	Benign	0.96	T;T
Polyphen		0.0010	B;B
Vest4		0.14
MutPred		0.28		Gain of ubiquitination at R38 (P = 0.0016);Gain of ubiquitination at R38 (P = 0.0016);
MVP		0.58
MPC		0.27
ClinPred		0.56	D
GERP RS		4.8
Varity_R		0.23
gMVP		0.41

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr13-46039284; COSMIC: COSV63073739; COSMIC: COSV63073739;