rs113455884

Variant names:

• chr16-70483921-G-T
• rs113455884
• NM_015386.3:c.1759C>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_015386.3(COG4):​c.1759C>A​(p.Gln587Lys) variant causes a missense change. The variant allele was found at a frequency of 0.0082 in 1,613,232 control chromosomes in the GnomAD database, including 79 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0051 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0085 (77 hom.)
• Consequence: COG4 NM_015386.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 3.76
• Publications: 6 publications found

Genes affected

COG4 (HGNC:18620): (component of oligomeric golgi complex 4) The protein encoded by this gene is a component of an oligomeric protein complex involved in the structure and function of the Golgi apparatus. Defects in this gene may be a cause of congenital disorder of glycosylation type IIj. Two transcript variants encoding different isoforms have been found for this gene.[provided by RefSeq, Aug 2010]

COG4 Gene-Disease associations (from GenCC):

• COG4-congenital disorder of glycosylation

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), G2P, ClinGen, PanelApp Australia, Ambry Genetics
• microcephalic osteodysplastic dysplasia, Saul-Wilson type

  Inheritance: AD, AR Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, Ambry Genetics, G2P

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.007169932).
• BP6: Variant 16-70483921-G-T is Benign according to our data. Variant chr16-70483921-G-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 95696.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00511 (778/152318) while in subpopulation NFE AF = 0.00889 (605/68028). AF 95% confidence interval is 0.00831. There are 2 homozygotes in GnomAd4. There are 364 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 2 AR,AD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_015386.3. 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
	COG4	NM_015386.3	MANE Select	c.1759C>A	p.Gln587Lys	missense	Exon 14 of 19	NP_056201.2
	COG4	NM_001195139.2		c.1684C>A	p.Gln562Lys	missense	Exon 13 of 18	NP_001182068.2
	COG4	NM_001365426.1		c.1333C>A	p.Gln445Lys	missense	Exon 15 of 20	NP_001352355.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COG4	ENST00000323786.10	TSL:1 MANE Select	c.1759C>A	p.Gln587Lys	missense	Exon 14 of 19	ENSP00000315775.5
	COG4	ENST00000393612.8	TSL:1	c.1696C>A	p.Gln566Lys	missense	Exon 13 of 18	ENSP00000377236.5
	COG4	ENST00000530314.5	TSL:1	n.2438C>A		non_coding_transcript_exon	Exon 12 of 17

Frequencies

GnomAD3 genomes AF: 0.00511 AC: 778 AN: 152200 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.00181

Gnomad AMI AF: 0.00219

Gnomad AMR AF: 0.00124

Gnomad ASJ AF: 0.00259

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.00290

Gnomad FIN AF: 0.00442

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00889

Gnomad OTH AF: 0.00239

GnomAD2 exomes AF: 0.00470 AC: 1178 AN: 250730 AF XY: 0.00484

Gnomad AFR exome AF: 0.00179

Gnomad AMR exome AF: 0.00110

Gnomad ASJ exome AF: 0.00249

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00278

Gnomad NFE exome AF: 0.00801

Gnomad OTH exome AF: 0.00392

GnomAD4 exome AF: 0.00852 AC: 12450 AN: 1460914 Hom.: 77 Cov.: 31 AF XY: 0.00840 AC XY: 6105 AN XY: 726764

African (AFR) AF: 0.00122 AC: 41 AN: 33480

American (AMR) AF: 0.000984 AC: 44 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.00233 AC: 61 AN: 26136

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.00311 AC: 268 AN: 86258

European-Finnish (FIN) AF: 0.00308 AC: 162 AN: 52522

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5768

European-Non Finnish (NFE) AF: 0.0103 AC: 11507 AN: 1111950

Other (OTH) AF: 0.00604 AC: 365 AN: 60382

GnomAD4 genome AF: 0.00511 AC: 778 AN: 152318 Hom.: 2 Cov.: 32 AF XY: 0.00489 AC XY: 364 AN XY: 74494

African (AFR) AF: 0.00180 AC: 75 AN: 41562

American (AMR) AF: 0.00124 AC: 19 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00259 AC: 9 AN: 3470

East Asian (EAS) AF: 0.000386 AC: 2 AN: 5180

South Asian (SAS) AF: 0.00290 AC: 14 AN: 4824

European-Finnish (FIN) AF: 0.00442 AC: 47 AN: 10628

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

European-Non Finnish (NFE) AF: 0.00889 AC: 605 AN: 68028

Other (OTH) AF: 0.00236 AC: 5 AN: 2116

Alfa AF: 0.00711 Hom.: 16

Bravo AF: 0.00435

TwinsUK AF: 0.0121 AC: 45

ALSPAC AF: 0.00934 AC: 36

ESP6500AA AF: 0.00136 AC: 6

ESP6500EA AF: 0.00791 AC: 68

ExAC AF: 0.00464 AC: 563

Asia WGS AF: 0.00202 AC: 8 AN: 3478

EpiCase AF: 0.00682

EpiControl AF: 0.00788

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	1	COG4-congenital disorder of glycosylation (1)
-	-	1	COG4-related disorder (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.059
BayesDel_addAF	Benign	-0.60	T
BayesDel_noAF	Benign	-0.62
CADD	Benign	17
DANN	Benign	0.86
DEOGEN2	Benign	0.0022	T
Eigen	Benign	-0.58
Eigen_PC	Benign	-0.30
FATHMM_MKL	Benign	0.41	N
LIST_S2	Benign	0.71	T
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.0072	T
MetaSVM	Benign	-1.0	T
PhyloP100		3.8
PrimateAI	Uncertain	0.60	T
PROVEAN	Benign	1.3	N
REVEL	Benign	0.091
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Vest4		0.34
MVP		0.099
MPC		0.19
ClinPred		0.0052	T
GERP RS		4.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
gMVP		0.39
Mutation Taster		=80/20	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: rs113455884; hg19: chr16-70517824;