NM_022457.7:c.1142-8delT

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BS1 BS2

The NM_022457.7(COP1):​c.1142-8delT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0165 in 90,924 control chromosomes in the GnomAD database, including 16 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 0.016 (16 hom., cov: 30)
  • Exomes 𝑓: 0.28 (3 hom.)
  • Failed GnomAD Quality Control
• 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.

• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0165 (1496/90924) while in subpopulation AFR AF = 0.0459 (1107/24106). AF 95% confidence interval is 0.0437. There are 16 homozygotes in GnomAd4. There are 728 alleles in the male GnomAd4 subpopulation. Median coverage is 30. This position passed quality control check.
• BS2: High AC in GnomAd4 at 1496 AD gene.

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.1142-8delT		splice_region intron	N/A	NP_071902.2
	COP1	NM_001001740.4		c.1070-8delT		splice_region intron	N/A	NP_001001740.1	Q8NHY2-2
	COP1	NM_001286644.2		c.422-8delT		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.1142-8delT		splice_region intron	N/A	ENSP00000356641.3	Q8NHY2-1
	COP1	ENST00000308769.12	TSL:1	c.1070-8delT		splice_region intron	N/A	ENSP00000310943.8	Q8NHY2-2
	COP1	ENST00000367667.5	TSL:1	n.*318-8delT		splice_region intron	N/A	ENSP00000356639.1	H0Y340

Frequencies

GnomAD3 genomes AF: 0.0164 AC: 1495 AN: 90916 Hom.: 16 Cov.: 30

Gnomad AFR AF: 0.0459

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00932

Gnomad ASJ AF: 0.0139

Gnomad EAS AF: 0.00467

Gnomad SAS AF: 0.0150

Gnomad FIN AF: 0.00523

Gnomad MID AF: 0.0234

Gnomad NFE AF: 0.00402

Gnomad OTH AF: 0.0169

GnomAD2 exomes AF: 0.370 AC: 38253 AN: 103470 AF XY: 0.371

Gnomad AFR exome AF: 0.369

Gnomad AMR exome AF: 0.368

Gnomad ASJ exome AF: 0.371

Gnomad EAS exome AF: 0.367

Gnomad FIN exome AF: 0.355

Gnomad NFE exome AF: 0.373

Gnomad OTH exome AF: 0.357

GnomAD4 exome Data not reliable, filtered out with message: InbreedingCoeff AF: 0.281 AC: 299729 AN: 1065664 Hom.: 3 Cov.: 0 AF XY: 0.282 AC XY: 149119 AN XY: 529004

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

African (AFR) AF: 0.297 AC: 6915 AN: 23258

American (AMR) AF: 0.296 AC: 6931 AN: 23446

Ashkenazi Jewish (ASJ) AF: 0.301 AC: 5401 AN: 17964

East Asian (EAS) AF: 0.326 AC: 9789 AN: 30060

South Asian (SAS) AF: 0.275 AC: 15180 AN: 55292

European-Finnish (FIN) AF: 0.279 AC: 9818 AN: 35246

Middle Eastern (MID) AF: 0.336 AC: 1395 AN: 4156

European-Non Finnish (NFE) AF: 0.278 AC: 231423 AN: 831866

Other (OTH) AF: 0.290 AC: 12877 AN: 44376

⚠️ 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: 0.0165 AC: 1496 AN: 90924 Hom.: 16 Cov.: 30 AF XY: 0.0172 AC XY: 728 AN XY: 42316

African (AFR) AF: 0.0459 AC: 1107 AN: 24106

American (AMR) AF: 0.00932 AC: 74 AN: 7944

Ashkenazi Jewish (ASJ) AF: 0.0139 AC: 33 AN: 2382

East Asian (EAS) AF: 0.00469 AC: 14 AN: 2984

South Asian (SAS) AF: 0.0145 AC: 45 AN: 3106

European-Finnish (FIN) AF: 0.00523 AC: 20 AN: 3822

Middle Eastern (MID) AF: 0.0250 AC: 3 AN: 120

European-Non Finnish (NFE) AF: 0.00402 AC: 180 AN: 44796

Other (OTH) AF: 0.0169 AC: 20 AN: 1186

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: COSV58171416; COSMIC: COSV58171416;