16-70496367-C-T

Position:

• chr16-70496367-C-T

Variant summary

Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PS1 PM2 PP3 PP5_Very_Strong

The NM_015386.3(COG4):​c.1546G>A​(p.Gly516Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Pathogenicin Lovd.

• Frequency: Genomes: not found (cov: 32)
• Consequence: COG4 NM_015386.3 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:7 O:1
• Conservation: PhyloP100: 7.71

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 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 15 ACMG points.

• PS1: Transcript NM_015386.3 (COG4) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in Lovd
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.824
• PP5: Variant 16-70496367-C-T is Pathogenic according to our data. Variant chr16-70496367-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 449730.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-70496367-C-T is described in Lovd as [Pathogenic]. Variant chr16-70496367-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COG4	NM_015386.3	c.1546G>A	p.Gly516Arg	missense_variant	12/19	ENST00000323786.10	NP_056201.2
COG4	NM_001195139.2	c.1534G>A	p.Gly512Arg	missense_variant	12/18		NP_001182068.2
COG4	NM_001365426.1	c.1120G>A	p.Gly374Arg	missense_variant	13/20		NP_001352355.1
COG4	NR_158212.1	n.1505G>A		non_coding_transcript_exon_variant	12/19

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COG4	ENST00000323786.10	c.1546G>A	p.Gly516Arg	missense_variant	12/19	1	NM_015386.3	ENSP00000315775.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:7 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Mar 31, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Oct 08, 2020	This variant appears to occur de novo in an individual tested at Athena Diagnostics and in multiple individuals with clinical features consistent with autosomal dominant Saul-Wilson syndrome (PMID 30290151). This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). Computational tools yielded predictions that this amino acid change may be damaging to the protein.This observation is not an independent occurrence and has been identified in the same individual by RCIGM, the other laboratory participating in the GEMINI study. -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Nov 23, 2022	Published functional studies demonstrate a significant increase in core proteins of HSPGs accumulation on the cell surface of G516R mutant cell lines and increased secretion of the SIL1 protein; findings which support a gain of function effect of the G516R variant (Sumya et al., 2021); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 34603392, 31949312, 30290151, 33688625, 34595172, 35455576, 36393834) -

Microcephalic osteodysplastic dysplasia, Saul-Wilson type Pathogenic:2 Other:1

Pathogenic, no assertion criteria provided	literature only	OMIM	Nov 29, 2018	- -
Pathogenic, criteria provided, single submitter	curation	SIB Swiss Institute of Bioinformatics	Jul 11, 2019	This variant is interpreted as a Pathogenic for Saul-Wilson syndrome, autosomal dominant. The following ACMG Tag(s) were applied: PM2; PS4-Moderate; PM6-Strong; PP3; PS3 -
not provided, no classification provided	literature only	GeneReviews	-	- -

Inborn genetic diseases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 17, 2021

The c.1546G>A (p.G516R) alteration is located in exon 12 (coding exon 12) of the COG4 gene. This alteration results from a G to A substitution at nucleotide position 1546, causing the glycine (G) at amino acid position 516 to be replaced by an arginine (R). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). The p.G516R alteration has been reported as a recurrent de novo alteration in several patients with Saul-Wilson syndrome (Ferreira, 2018). This amino acid position is highly conserved in available vertebrate species. Fibroblasts from patients with the p.G516R alteration have been shown to have abnormal Golgi morphology and decreased Golgi volume compared to control samples. Glycan analysis and glycosylation status were not measurably different between patients and controls; however there was evidence of altered Golgi-dependent glycosylation and abnormal Golgi trafficking in patients (Ferreira, 2018) . The in silico prediction for this alteration is inconclusive. Based on the available evidence, this alteration is classified as pathogenic. -

COG4-congenital disorder of glycosylation Pathogenic:1

Pathogenic, criteria provided, single submitter

research

Undiagnosed Diseases Network, NIH

Aug 23, 2017

This individual has been reported in PMID: 30290151. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.22	D
BayesDel_noAF	Uncertain	0.080
CADD	Uncertain	25
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.049	T;T
Eigen	Pathogenic	0.76
Eigen_PC	Pathogenic	0.79
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.97	D;D
M_CAP	Benign	0.047	D
MetaRNN	Pathogenic	0.82	D;D
MetaSVM	Benign	-0.66	T
PrimateAI	Pathogenic	0.86	D
PROVEAN	Benign	-1.7	N;.
REVEL	Uncertain	0.38
Sift	Benign	0.045	D;.
Sift4G	Benign	0.12	T;T
Vest4		0.91
MVP		0.68
MPC		0.70
ClinPred		0.98	D
GERP RS		6.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
gMVP		0.79

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: rs1555575860; hg19: chr16-70530270; COSMIC: COSV60421914; COSMIC: COSV60421914;