rs183569708

Positions:

• chr16-70508462-G-A

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_015386.3(COG4):​c.1005C>T​(p.Phe335Phe) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000191 in 1,613,822 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00020 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00019 (2 hom.)
• Consequence: COG4 NM_015386.3 splice_region, synonymous
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 1.54

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 Benign. Variant got -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.28).
• BP6: Variant 16-70508462-G-A is Benign according to our data. Variant chr16-70508462-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 471471.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=1.54 with no splicing effect.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.000197 (30/152230) while in subpopulation SAS AF= 0.000831 (4/4814). AF 95% confidence interval is 0.000284. There are 1 homozygotes in gnomad4. There are 14 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COG4	NM_015386.3	c.1005C>T	p.Phe335Phe	splice_region_variant, synonymous_variant	8/19	ENST00000323786.10	NP_056201.2
COG4	NM_001195139.2	c.993C>T	p.Phe331Phe	splice_region_variant, synonymous_variant	8/18		NP_001182068.2
COG4	NM_001365426.1	c.579C>T	p.Phe193Phe	splice_region_variant, synonymous_variant	9/20		NP_001352355.1
COG4	NR_158212.1	n.1016C>T		splice_region_variant, non_coding_transcript_exon_variant	8/19

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COG4	ENST00000323786.10	c.1005C>T	p.Phe335Phe	splice_region_variant, synonymous_variant	8/19	1	NM_015386.3	ENSP00000315775.5

Frequencies

GnomAD3 genomes AF: 0.000164 AC: 25 AN: 152112 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000328

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.000830

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000147

Gnomad OTH AF: 0.00239

GnomAD3 exomes AF: 0.000239 AC: 60 AN: 251450 Hom.: 0 AF XY: 0.000302 AC XY: 41 AN XY: 135902

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000260

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00114

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000879

Gnomad OTH exome AF: 0.000978

GnomAD4 exome AF: 0.000191 AC: 279 AN: 1461592 Hom.: 2 Cov.: 30 AF XY: 0.000242 AC XY: 176 AN XY: 727120

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000201

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000101

Gnomad4 SAS exome AF: 0.00158

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000639

Gnomad4 OTH exome AF: 0.000927

GnomAD4 genome AF: 0.000197 AC: 30 AN: 152230 Hom.: 1 Cov.: 32 AF XY: 0.000188 AC XY: 14 AN XY: 74424

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.000327

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.000831

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000147

Gnomad4 OTH AF: 0.00473

Alfa AF: 0.000323 Hom.: 0

Bravo AF: 0.0000982

Asia WGS AF: 0.0130 AC: 45 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.000119

ClinVar

Significance: Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

COG4-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 22, 2020

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Apr 01, 2023

COG4: BP4, BP7 -

COG4-congenital disorder of glycosylation Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 03, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.28
CADD	Benign	11
DANN	Benign	0.83

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: rs183569708; hg19: chr16-70542365; COSMIC: COSV60424992; COSMIC: COSV60424992;