1-176081294-GAAAAAAAA-GAAAAAAAAA

Variant names:

• chr1-176081294-G-GA
• rs56720201
• NM_022457.7:c.1142-8dupT

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BA1

The NM_022457.7(COP1):​c.1142-8dupT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0838 in 1,255,060 control chromosomes in the GnomAD database, including 117 homozygotes. 1/1 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.049 (96 hom., cov: 30)
  • Exomes 𝑓: 0.087 (21 hom.)
• Consequence: COP1 NM_022457.7 splice_region, intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.493
• Publications: 1 publications found

Genes affected

COP1 (HGNC:17440): (COP1 E3 ubiquitin ligase) Enables ubiquitin protein ligase activity. Involved in positive regulation of proteasomal ubiquitin-dependent protein catabolic process; proteasome-mediated ubiquitin-dependent protein catabolic process; and response to ionizing radiation. Part of Cul4A-RING E3 ubiquitin ligase complex. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Benign. The variant received -8 ACMG points.

• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0609 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_022457.7. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COP1	NM_022457.7	MANE Select	c.1142-8dupT		splice_region intron	N/A	NP_071902.2
	COP1	NM_001001740.4		c.1070-8dupT		splice_region intron	N/A	NP_001001740.1	Q8NHY2-2
	COP1	NM_001286644.2		c.422-8dupT		splice_region intron	N/A	NP_001273573.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COP1	ENST00000367669.8	TSL:1 MANE Select	c.1142-8_1142-7insT		splice_region intron	N/A	ENSP00000356641.3	Q8NHY2-1
	COP1	ENST00000308769.12	TSL:1	c.1070-8_1070-7insT		splice_region intron	N/A	ENSP00000310943.8	Q8NHY2-2
	COP1	ENST00000367667.5	TSL:1	n.*318-8_*318-7insT		splice_region intron	N/A	ENSP00000356639.1	H0Y340

Frequencies

GnomAD3 genomes AF: 0.0493 AC: 4477 AN: 90862 Hom.: 96 Cov.: 30

Gnomad AFR AF: 0.0318

Gnomad AMI AF: 0.0485

Gnomad AMR AF: 0.0362

Gnomad ASJ AF: 0.0390

Gnomad EAS AF: 0.00434

Gnomad SAS AF: 0.0301

Gnomad FIN AF: 0.0840

Gnomad MID AF: 0.0625

Gnomad NFE AF: 0.0628

Gnomad OTH AF: 0.0508

GnomAD2 exomes AF: 0.0788 AC: 8151 AN: 103470 AF XY: 0.0783

Gnomad AFR exome AF: 0.0809

Gnomad AMR exome AF: 0.0711

Gnomad ASJ exome AF: 0.0740

Gnomad EAS exome AF: 0.0887

Gnomad FIN exome AF: 0.0855

Gnomad NFE exome AF: 0.0813

Gnomad OTH exome AF: 0.0896

GnomAD4 exome AF: 0.0865 AC: 100711 AN: 1164190 Hom.: 21 Cov.: 0 AF XY: 0.0854 AC XY: 49417 AN XY: 578344

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

African (AFR) AF: 0.0721 AC: 1842 AN: 25562

American (AMR) AF: 0.0665 AC: 1702 AN: 25576

Ashkenazi Jewish (ASJ) AF: 0.0661 AC: 1297 AN: 19612

East Asian (EAS) AF: 0.0492 AC: 1693 AN: 34406

South Asian (SAS) AF: 0.0784 AC: 4607 AN: 58764

European-Finnish (FIN) AF: 0.0763 AC: 2965 AN: 38868

Middle Eastern (MID) AF: 0.0497 AC: 234 AN: 4704

European-Non Finnish (NFE) AF: 0.0910 AC: 82623 AN: 908116

Other (OTH) AF: 0.0771 AC: 3748 AN: 48582

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0493 AC: 4483 AN: 90870 Hom.: 96 Cov.: 30 AF XY: 0.0501 AC XY: 2120 AN XY: 42302

African (AFR) AF: 0.0318 AC: 767 AN: 24086

American (AMR) AF: 0.0365 AC: 290 AN: 7944

Ashkenazi Jewish (ASJ) AF: 0.0390 AC: 93 AN: 2386

East Asian (EAS) AF: 0.00436 AC: 13 AN: 2982

South Asian (SAS) AF: 0.0306 AC: 95 AN: 3102

European-Finnish (FIN) AF: 0.0840 AC: 321 AN: 3820

Middle Eastern (MID) AF: 0.0667 AC: 8 AN: 120

European-Non Finnish (NFE) AF: 0.0628 AC: 2813 AN: 44772

Other (OTH) AF: 0.0507 AC: 60 AN: 1184

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.49
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs56720201; hg19: chr1-176050430; COSMIC: COSV58162736; COSMIC: COSV58162736;