17-73208301-C-T

Position:

• chr17-73208301-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_018714.3(COG1):​c.2806-13C>T variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00446 in 1,613,064 control chromosomes in the GnomAD database, including 31 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0037 (5 hom., cov: 33)
  • Exomes 𝑓: 0.0045 (26 hom.)
• Consequence: COG1 NM_018714.3 splice_polypyrimidine_tract, intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.0290

Genes affected

FAM104A (HGNC:25918): (VCP nuclear cofactor family member 1)

COG1 (HGNC:6545): (component of oligomeric golgi complex 1) The protein encoded by this gene is one of eight proteins (Cog1-8) which form a Golgi-localized complex (COG) required for normal Golgi morphology and function. It is thought that this protein is required for steps in the normal medial and trans Golgi-associated processing of glycoconjugates and plays a role in the organization of the Golgi-localized complex. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.56).
• BP6: Variant 17-73208301-C-T is Benign according to our data. Variant chr17-73208301-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 324977.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00373 (568/152392) while in subpopulation AMR AF= 0.00921 (141/15310). AF 95% confidence interval is 0.00797. There are 5 homozygotes in gnomad4. There are 284 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FAM104A	NM_001098832.2	c.*1228G>A		3_prime_UTR_variant	4/4	ENST00000405159.8
COG1	NM_018714.3	c.2806-13C>T		splice_polypyrimidine_tract_variant, intron_variant		ENST00000299886.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FAM104A	ENST00000405159.8	c.*1228G>A		3_prime_UTR_variant	4/4	1	NM_001098832.2
COG1	ENST00000299886.9	c.2806-13C>T		splice_polypyrimidine_tract_variant, intron_variant		1	NM_018714.3	P1

Frequencies

GnomAD3 genomes AF: 0.00373 AC: 568 AN: 152274 Hom.: 5 Cov.: 33

Gnomad AFR AF: 0.00157

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00922

Gnomad ASJ AF: 0.00317

Gnomad EAS AF: 0.00192

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00264

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00444

Gnomad OTH AF: 0.00430

GnomAD3 exomes AF: 0.00544 AC: 1367 AN: 251396 Hom.: 10 AF XY: 0.00489 AC XY: 665 AN XY: 135874

Gnomad AFR exome AF: 0.00148

Gnomad AMR exome AF: 0.0159

Gnomad ASJ exome AF: 0.00218

Gnomad EAS exome AF: 0.000381

Gnomad SAS exome AF: 0.00108

Gnomad FIN exome AF: 0.00454

Gnomad NFE exome AF: 0.00536

Gnomad OTH exome AF: 0.00391

GnomAD4 exome AF: 0.00454 AC: 6626 AN: 1460672 Hom.: 26 Cov.: 32 AF XY: 0.00434 AC XY: 3151 AN XY: 726684

Gnomad4 AFR exome AF: 0.000927

Gnomad4 AMR exome AF: 0.0142

Gnomad4 ASJ exome AF: 0.00214

Gnomad4 EAS exome AF: 0.000831

Gnomad4 SAS exome AF: 0.00129

Gnomad4 FIN exome AF: 0.00497

Gnomad4 NFE exome AF: 0.00472

Gnomad4 OTH exome AF: 0.00391

GnomAD4 genome AF: 0.00373 AC: 568 AN: 152392 Hom.: 5 Cov.: 33 AF XY: 0.00381 AC XY: 284 AN XY: 74526

Gnomad4 AFR AF: 0.00156

Gnomad4 AMR AF: 0.00921

Gnomad4 ASJ AF: 0.00317

Gnomad4 EAS AF: 0.00193

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.00264

Gnomad4 NFE AF: 0.00442

Gnomad4 OTH AF: 0.00473

Alfa AF: 0.00366 Hom.: 0

Bravo AF: 0.00399

Asia WGS AF: 0.00866 AC: 30 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

COG1 congenital disorder of glycosylation Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 25, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	May 04, 2021	See Variant Classification Assertion Criteria. -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.56
CADD	Benign	16
DANN	Benign	0.88
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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: rs141573449; hg19: chr17-71204440;