chr16-70496367-C-G

Variant names:

• chr16-70496367-C-G
• rs1555575860
• NM_015386.3:c.1546G>C

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PS1_Very_Strong PM2 PP3 PP5

The NM_015386.3(COG4):​c.1546G>C​(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 (no stars). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Pathogenic in ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: COG4 NM_015386.3 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1 O:1
• Conservation: PhyloP100: 7.71
• Publications: 1 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: Pathogenic. The variant received 12 ACMG points.

• PS1: Transcript NM_015386.3 (COG4) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar.
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.825
• PP5: Variant 16-70496367-C-G is Pathogenic according to our data. Variant chr16-70496367-C-G is described in ClinVar as Pathogenic. ClinVar VariationId is 585271.Status of the report is no_assertion_criteria_provided, 0 stars.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COG4	NM_015386.3	MANE Select	c.1546G>C	p.Gly516Arg	missense	Exon 12 of 19	NP_056201.2
	COG4	NM_001195139.2		c.1534G>C	p.Gly512Arg	missense	Exon 12 of 18	NP_001182068.2
	COG4	NM_001365426.1		c.1120G>C	p.Gly374Arg	missense	Exon 13 of 20	NP_001352355.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COG4	ENST00000323786.10	TSL:1 MANE Select	c.1546G>C	p.Gly516Arg	missense	Exon 12 of 19	ENSP00000315775.5
	COG4	ENST00000393612.8	TSL:1	c.1546G>C	p.Gly516Arg	missense	Exon 12 of 18	ENSP00000377236.5
	COG4	ENST00000530314.5	TSL:1	n.2225G>C		non_coding_transcript_exon	Exon 10 of 17

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1 Other:1

Revision: no assertion criteria provided

Submissions by phenotype

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

Nov 29, 2018

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.94
BayesDel_addAF	Pathogenic	0.22	D
BayesDel_noAF	Uncertain	0.080
CADD	Uncertain	24
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.049	T
Eigen	Pathogenic	0.77
Eigen_PC	Pathogenic	0.80
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.97	D
M_CAP	Benign	0.049	D
MetaRNN	Pathogenic	0.83	D
MetaSVM	Benign	-0.64	T
PhyloP100		7.7
PrimateAI	Pathogenic	0.86	D
PROVEAN	Benign	-1.7	N
REVEL	Uncertain	0.37
Sift	Benign	0.045	D
Sift4G	Benign	0.12	T
Vest4		0.91
MVP		0.68
MPC		0.70
ClinPred		0.98	D
GERP RS		6.0
gMVP		0.79
Mutation Taster		=13/87	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs1555575860; hg19: chr16-70530270;