1-176081294-GAAAAAAAA-GAAAAAA

Variant names:

• chr1-176081294-GAA-G
• rs56720201
• NM_022457.7:c.1142-9_1142-8delTT

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 0P and 0B.

The NM_022457.7(COP1):​c.1142-9_1142-8delTT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0253 in 1,204,772 control chromosomes in the GnomAD database, with no homozygous occurrence. There is a variant allele frequency bias in the population database for this variant (GnomAd4), which may indicate mosaicism or somatic mutations in the reference population data. 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 0.00015 (0 hom., cov: 30)
  • Exomes 𝑓: 0.027 (0 hom.)
• Consequence: COP1 NM_022457.7 splice_region, intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.59
• 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: Uncertain_significance. The variant received 0 ACMG points.

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.1142-9_1142-8delTT		splice_region intron	N/A	NP_071902.2
	COP1	NM_001001740.4		c.1070-9_1070-8delTT		splice_region intron	N/A	NP_001001740.1	Q8NHY2-2
	COP1	NM_001286644.2		c.422-9_422-8delTT		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.1142-9_1142-8delTT		splice_region intron	N/A	ENSP00000356641.3	Q8NHY2-1
	COP1	ENST00000308769.12	TSL:1	c.1070-9_1070-8delTT		splice_region intron	N/A	ENSP00000310943.8	Q8NHY2-2
	COP1	ENST00000367667.5	TSL:1	n.*318-9_*318-8delTT		splice_region intron	N/A	ENSP00000356639.1	H0Y340

Frequencies

GnomAD3 genomes AF: 0.000154 AC: 14 AN: 90950 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.0000415

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000126

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00157

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000134

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0366 AC: 3788 AN: 103470 AF XY: 0.0365

Gnomad AFR exome AF: 0.0353

Gnomad AMR exome AF: 0.0481

Gnomad ASJ exome AF: 0.0462

Gnomad EAS exome AF: 0.0326

Gnomad FIN exome AF: 0.0254

Gnomad NFE exome AF: 0.0329

Gnomad OTH exome AF: 0.0380

GnomAD4 exome AF: 0.0273 AC: 30418 AN: 1113814 Hom.: 0 AF XY: 0.0283 AC XY: 15676 AN XY: 552972

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

African (AFR) AF: 0.0295 AC: 720 AN: 24416

American (AMR) AF: 0.0416 AC: 1009 AN: 24274

Ashkenazi Jewish (ASJ) AF: 0.0348 AC: 643 AN: 18462

East Asian (EAS) AF: 0.0293 AC: 946 AN: 32276

South Asian (SAS) AF: 0.0434 AC: 2421 AN: 55768

European-Finnish (FIN) AF: 0.0319 AC: 1179 AN: 37008

Middle Eastern (MID) AF: 0.0229 AC: 102 AN: 4454

European-Non Finnish (NFE) AF: 0.0252 AC: 21985 AN: 870856

Other (OTH) AF: 0.0305 AC: 1413 AN: 46300

⚠️ 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: 0.000154 AC: 14 AN: 90958 Hom.: 0 Cov.: 30 AF XY: 0.000118 AC XY: 5 AN XY: 42334

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

African (AFR) AF: 0.0000415 AC: 1 AN: 24114

American (AMR) AF: 0.000126 AC: 1 AN: 7948

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2386

East Asian (EAS) AF: 0.00 AC: 0 AN: 2984

South Asian (SAS) AF: 0.00 AC: 0 AN: 3106

European-Finnish (FIN) AF: 0.00157 AC: 6 AN: 3822

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 120

European-Non Finnish (NFE) AF: 0.000134 AC: 6 AN: 44816

Other (OTH) AF: 0.00 AC: 0 AN: 1184

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.6
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;