NM_153603.4:c.1476-1G>T

Variant names:

• chr16-23406263-C-A
• rs1555493029
• NM_153603.4:c.1476-1G>T

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_153603.4(COG7):​c.1476-1G>T variant causes a splice acceptor, intron 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. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: COG7 NM_153603.4 splice_acceptor, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 7.91

Genes affected

COG7 (HGNC:18622): (component of oligomeric golgi complex 7) The protein encoded by this gene resides in the golgi, and constitutes one of the 8 subunits of the conserved oligomeric Golgi (COG) complex, which is required for normal golgi morphology and localization. Mutations in this gene are associated with the congenital disorder of glycosylation type IIe.[provided by RefSeq, May 2010]

ACMG classification

Verdict is Pathogenic. Variant got 12 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, Cryptic splice site detected, with MaxEntScore 9.1, offset of 14, new splice context is: ttacatgattttgtccacAGctg. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 16-23406263-C-A is Pathogenic according to our data. Variant chr16-23406263-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 548708.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COG7	NM_153603.4	c.1476-1G>T		splice_acceptor_variant, intron_variant	Intron 11 of 16	ENST00000307149.10	NP_705831.1
COG7	XM_017023870.2	c.1281-1G>T		splice_acceptor_variant, intron_variant	Intron 11 of 16		XP_016879359.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COG7	ENST00000307149.10	c.1476-1G>T		splice_acceptor_variant, intron_variant	Intron 11 of 16	1	NM_153603.4	ENSP00000305442.5
COG7	ENST00000567821.1	n.511-1G>T		splice_acceptor_variant, intron_variant	Intron 3 of 5	5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

COG7 congenital disorder of glycosylation Pathogenic:1

Jun 29, 2018

Medical Genetics Lab, Policlinico S. Orsola.Malpighi

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Null variant (within ±2 of canonical splice site) affecting gene COG7, which is a known mechanism of disease. Allele is not found in Broad gnomAD exomes despite of good coverage=90 (greater than 20). Computational verdict is pathogenic because 3 pathogenic predictions from DANN, GERP and MutationTaster (vs no benign predictions). This patient carries a second likely pathogenic variant of COG7 in compound heterozygosity: c.2T>C, p.Met1Thr. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.41
CADD	Pathogenic	34
DANN	Uncertain	1.0
Eigen	Pathogenic	1.2
Eigen_PC	Pathogenic	1.1
FATHMM_MKL	Pathogenic	0.99	D
GERP RS		5.7

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.94
SpliceAI score (max)		0.99		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.81		Position offset: -15
DS_AL_spliceai		0.99		Position offset: -1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1555493029; hg19: chr16-23417584; COSMIC: COSV100207508;