13-45503246-G-C

Variant names:

• chr13-45503246-G-C
• rs3014960
• NM_031431.4:c.1491G>C

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_031431.4(COG3):​c.1491G>C​(p.Gln497His) variant causes a missense, splice region change. The variant was absent in control chromosomes in GnomAD project. 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: COG3 NM_031431.4 missense, splice_region
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.57
• Publications: 20 publications found

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

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.33191645).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COG3	NM_031431.4	c.1491G>C	p.Gln497His	missense_variant, splice_region_variant	Exon 14 of 23	ENST00000349995.10	NP_113619.3
COG3	XM_047430702.1	c.1491G>C	p.Gln497His	missense_variant, splice_region_variant	Exon 14 of 19		XP_047286658.1
COG3	XR_007063702.1	n.1428G>C		splice_region_variant, non_coding_transcript_exon_variant	Exon 13 of 14
COG3	XR_429222.5	n.1589G>C		splice_region_variant, non_coding_transcript_exon_variant	Exon 14 of 24

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COG3	ENST00000349995.10	c.1491G>C	p.Gln497His	missense_variant, splice_region_variant	Exon 14 of 23	1	NM_031431.4	ENSP00000258654.8
COG3	ENST00000465942.1	n.466G>C		splice_region_variant, non_coding_transcript_exon_variant	Exon 5 of 7	3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1379638 Hom.: 0 Cov.: 21 AF XY: 0.00 AC XY: 0 AN XY: 691318

African (AFR) AF: 0.00 AC: 0 AN: 31762

American (AMR) AF: 0.00 AC: 0 AN: 44576

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25592

East Asian (EAS) AF: 0.00 AC: 0 AN: 39338

South Asian (SAS) AF: 0.00 AC: 0 AN: 84446

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53366

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5306

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1037610

Other (OTH) AF: 0.00 AC: 0 AN: 57642

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.030	T
Eigen	Benign	-0.26
Eigen_PC	Benign	-0.079
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.92	D
M_CAP	Benign	0.024	T
MetaRNN	Benign	0.33	T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	1.6	L
PhyloP100		5.6
PrimateAI	Uncertain	0.55	T
PROVEAN	Benign	-1.4	N
REVEL	Benign	0.062
Sift	Benign	0.049	D
Sift4G	Benign	0.092	T
Polyphen		0.29	B
Vest4		0.17
MutPred		0.39		Gain of catalytic residue at I498 (P = 0.0059);
MVP		0.30
MPC		0.33
ClinPred		0.87	D
GERP RS		4.8
Varity_R		0.052
gMVP		0.24
Mutation Taster		=69/31	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: rs3014960; hg19: chr13-46077381;