rs375280565

Variant names:

• chr13-39724499-TTTA-T
• rs375280565
• NM_020751.3:c.1693-8_1693-6delTTA

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP6_Moderate BS2

The NM_020751.3(COG6):​c.1693-8_1693-6delTTA variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00473 in 1,317,946 control chromosomes in the GnomAD database, including 3 homozygotes. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.00011 (0 hom., cov: 0)
  • Exomes 𝑓: 0.0047 (3 hom.)
  • Failed GnomAD Quality Control
• Consequence: COG6 NM_020751.3 splice_region, intron
• Clinical Significance: Benign criteria provided, single submitter B:2
• Conservation: PhyloP100: 0.232
• Publications: 0 publications found

Genes affected

COG6 (HGNC:18621): (component of oligomeric golgi complex 6) This gene encodes a subunit of the conserved oligomeric Golgi complex that is required for maintaining normal structure and activity of the Golgi apparatus. The encoded protein is organized with conserved oligomeric Golgi complex components 5, 7 and 8 into a sub-complex referred to as lobe B. Alternative splicing results in multiple transcript variants.[provided by RefSeq, Feb 2009]

COG6 Gene-Disease associations (from GenCC):

• COG6-congenital disorder of glycosylation

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: PanelApp Australia, Orphanet, Labcorp Genetics (formerly Invitae)
• hypohidrosis-enamel hypoplasia-palmoplantar keratoderma-intellectual disability syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_benign. The variant received -6 ACMG points.

• BP6: Variant 13-39724499-TTTA-T is Benign according to our data. Variant chr13-39724499-TTTA-T is described in ClinVar as [Benign]. Clinvar id is 540362.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Homozygotes in GnomAdExome4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COG6	NM_020751.3	c.1693-8_1693-6delTTA		splice_region_variant, intron_variant	Intron 16 of 18	ENST00000455146.8	NP_065802.1
COG6	NM_001145079.2	c.1693-8_1693-6delTTA		splice_region_variant, intron_variant	Intron 16 of 18		NP_001138551.1
COG6	NR_026745.1	n.1858-8_1858-6delTTA		splice_region_variant, intron_variant	Intron 17 of 19
COG6	XM_011535168.2	c.1693-8_1693-6delTTA		splice_region_variant, intron_variant	Intron 16 of 19		XP_011533470.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COG6	ENST00000455146.8	c.1693-8_1693-6delTTA		splice_region_variant, intron_variant	Intron 16 of 18	1	NM_020751.3	ENSP00000397441.2
COG6	ENST00000416691.6	c.1693-8_1693-6delTTA		splice_region_variant, intron_variant	Intron 16 of 18	1		ENSP00000403733.1
COG6	ENST00000356576.8	n.*1530-8_*1530-6delTTA		splice_region_variant, intron_variant	Intron 17 of 19	1		ENSP00000348983.4

Frequencies

GnomAD3 genomes AF: 0.000108 AC: 14 AN: 129554 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.0000560

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000640

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000106

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000663

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00936 AC: 1984 AN: 211854 AF XY: 0.00928

Gnomad AFR exome AF: 0.00828

Gnomad AMR exome AF: 0.0147

Gnomad ASJ exome AF: 0.00545

Gnomad EAS exome AF: 0.00992

Gnomad FIN exome AF: 0.00516

Gnomad NFE exome AF: 0.00898

Gnomad OTH exome AF: 0.00951

GnomAD4 exome AF: 0.00473 AC: 6231 AN: 1317946 Hom.: 3 AF XY: 0.00474 AC XY: 3113 AN XY: 656884

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00411 AC: 122 AN: 29698

American (AMR) AF: 0.0105 AC: 386 AN: 36634

Ashkenazi Jewish (ASJ) AF: 0.00507 AC: 117 AN: 23084

East Asian (EAS) AF: 0.00531 AC: 186 AN: 35018

South Asian (SAS) AF: 0.00680 AC: 503 AN: 73952

European-Finnish (FIN) AF: 0.00294 AC: 147 AN: 50066

Middle Eastern (MID) AF: 0.00967 AC: 42 AN: 4342

European-Non Finnish (NFE) AF: 0.00442 AC: 4470 AN: 1011088

Other (OTH) AF: 0.00477 AC: 258 AN: 54064

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.000108 AC: 14 AN: 129554 Hom.: 0 Cov.: 0 AF XY: 0.000127 AC XY: 8 AN XY: 62878

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0000560 AC: 2 AN: 35696

American (AMR) AF: 0.000640 AC: 7 AN: 10940

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2878

East Asian (EAS) AF: 0.00 AC: 0 AN: 4148

South Asian (SAS) AF: 0.00 AC: 0 AN: 3394

European-Finnish (FIN) AF: 0.000106 AC: 1 AN: 9426

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 276

European-Non Finnish (NFE) AF: 0.0000663 AC: 4 AN: 60298

Other (OTH) AF: 0.00 AC: 0 AN: 1684

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.000018), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.000169 Hom.: 0

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, single submitter

Submissions by phenotype

COG6-related disorder Benign:1

Mar 30, 2020

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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

COG6-congenital disorder of glycosylation;C3809160:Hypohidrosis-enamel hypoplasia-palmoplantar keratoderma-intellectual disability syndrome Benign:1

Jan 07, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.23
Mutation Taster		=96/4	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs375280565; hg19: chr13-40298636; COSMIC: COSV62997612;