rs3931036

chr16-70514394-G-Achr16-70514394-G-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_015386.3(COG4):c.485C>T(p.Thr162Ile) variant causes a missense change. The variant allele was found at a frequency of 0.941 in 1,613,988 control chromosomes in the GnomAD database, including 714,932 homozygotes. In-silico tool predicts a benign outcome for this variant. 10/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T162V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.95 (69365 hom., cov: 30)
  • Exomes 𝑓: 0.94 (645567 hom.)
• Consequence: COG4 NM_015386.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 7.02

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=5.8243927E-7).
• BP6: Variant 16-70514394-G-A is Benign according to our data. Variant chr16-70514394-G-A is described in ClinVar as [Benign]. Clinvar id is 95697.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-70514394-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.981 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COG4	NM_015386.3	c.485C>T	p.Thr162Ile	missense_variant	4/19	ENST00000323786.10
COG4	NM_001195139.2	c.473C>T	p.Thr158Ile	missense_variant	4/18
COG4	NM_001365426.1	c.59C>T	p.Thr20Ile	missense_variant	5/20
COG4	NR_158212.1	n.496C>T		non_coding_transcript_exon_variant	4/19

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COG4	ENST00000323786.10	c.485C>T	p.Thr162Ile	missense_variant	4/19	1	NM_015386.3	P1

Frequencies

GnomAD3 genomes AF: 0.954 AC: 145106 AN: 152086 Hom.: 69305 Cov.: 30

Gnomad AFR AF: 0.989

Gnomad AMI AF: 0.934

Gnomad AMR AF: 0.923

Gnomad ASJ AF: 0.947

Gnomad EAS AF: 0.999

Gnomad SAS AF: 0.964

Gnomad FIN AF: 0.943

Gnomad MID AF: 0.978

Gnomad NFE AF: 0.937

Gnomad OTH AF: 0.963

GnomAD3 exomes AF: 0.945 AC: 237617 AN: 251324 Hom.: 112444 AF XY: 0.947 AC XY: 128581 AN XY: 135840

Gnomad AFR exome AF: 0.991

Gnomad AMR exome AF: 0.899

Gnomad ASJ exome AF: 0.955

Gnomad EAS exome AF: 1.00

Gnomad SAS exome AF: 0.958

Gnomad FIN exome AF: 0.945

Gnomad NFE exome AF: 0.939

Gnomad OTH exome AF: 0.955

GnomAD4 exome AF: 0.940 AC: 1373357 AN: 1461784 Hom.: 645567 Cov.: 52 AF XY: 0.940 AC XY: 683429 AN XY: 727196

Gnomad4 AFR exome AF: 0.991

Gnomad4 AMR exome AF: 0.899

Gnomad4 ASJ exome AF: 0.955

Gnomad4 EAS exome AF: 1.00

Gnomad4 SAS exome AF: 0.957

Gnomad4 FIN exome AF: 0.947

Gnomad4 NFE exome AF: 0.935

Gnomad4 OTH exome AF: 0.949

GnomAD4 genome AF: 0.954 AC: 145224 AN: 152204 Hom.: 69365 Cov.: 30 AF XY: 0.955 AC XY: 71078 AN XY: 74412

Gnomad4 AFR AF: 0.989

Gnomad4 AMR AF: 0.923

Gnomad4 ASJ AF: 0.947

Gnomad4 EAS AF: 0.999

Gnomad4 SAS AF: 0.964

Gnomad4 FIN AF: 0.943

Gnomad4 NFE AF: 0.937

Gnomad4 OTH AF: 0.964

Alfa AF: 0.945 Hom.: 165139

Bravo AF: 0.954

TwinsUK AF: 0.924 AC: 3428

ALSPAC AF: 0.928 AC: 3575

ESP6500AA AF: 0.987 AC: 4339

ESP6500EA AF: 0.940 AC: 8080

ExAC AF: 0.947 AC: 115010

Asia WGS AF: 0.980 AC: 3409 AN: 3478

EpiCase AF: 0.942

EpiControl AF: 0.947

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 02, 2015	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	May 28, 2013	- -
Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

COG4-congenital disorder of glycosylation Benign:3

Benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 22, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -

Microcephalic osteodysplastic dysplasia, Saul-Wilson type Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 22, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.49	T
BayesDel_noAF	Benign	-0.41
Cadd	Benign	16
Dann	Benign	0.11
DEOGEN2	Benign	0.0040	T;T;.;T
Eigen	Benign	-0.79
Eigen_PC	Benign	-0.44
FATHMM_MKL	Benign	0.28	N
LIST_S2	Benign	0.44	T;T;T;T
MetaRNN	Benign	5.8e-7	T;T;T;T
MetaSVM	Benign	-0.95	T
MutationTaster	Benign	1.0	P;P;P
PrimateAI	Pathogenic	0.84	D
PROVEAN	Benign	3.7	N;.;N;.
REVEL	Benign	0.26
Sift	Benign	1.0	T;.;T;.
Sift4G	Benign	1.0	T;T;T;.
Vest4		0.22
MPC		0.16
ClinPred		0.0099	T
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
gMVP		0.12

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

LitVar

Other links and lift over

dbSNP: rs3931036; hg19: chr16-70548297;