1-176081294-GAAAAAAAA-GAAAAA

Variant names:

• chr1-176081294-GAAA-G
• rs56720201
• NM_022457.7:c.1142-10_1142-8delTTT

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP6_Moderate

The NM_022457.7(COP1):​c.1142-10_1142-8delTTT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00371 in 1,257,576 control chromosomes in the GnomAD database, with no homozygous occurrence. There is a variant allele frequency bias in the population database for this variant (GnomAdExome4), which may indicate mosaicism or somatic mutations in the reference population data. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 30)
  • Exomes 𝑓: 0.0040 (0 hom.)
• Consequence: COP1 NM_022457.7 splice_region, intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• 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: Likely_benign. The variant received -2 ACMG points.

• BP6: Variant 1-176081294-GAAA-G is Benign according to our data. Variant chr1-176081294-GAAA-G is described in ClinVar as Benign. ClinVar VariationId is 788692.Status of the report is criteria_provided_single_submitter, 1 stars.

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.1142-10_1142-8delTTT		splice_region intron	N/A	NP_071902.2
	COP1	NM_001001740.4		c.1070-10_1070-8delTTT		splice_region intron	N/A	NP_001001740.1	Q8NHY2-2
	COP1	NM_001286644.2		c.422-10_422-8delTTT		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.1142-10_1142-8delTTT		splice_region intron	N/A	ENSP00000356641.3	Q8NHY2-1
	COP1	ENST00000308769.12	TSL:1	c.1070-10_1070-8delTTT		splice_region intron	N/A	ENSP00000310943.8	Q8NHY2-2
	COP1	ENST00000367667.5	TSL:1	n.*318-10_*318-8delTTT		splice_region intron	N/A	ENSP00000356639.1	H0Y340

Frequencies

GnomAD3 genomes AF: 0.0000330 AC: 3 AN: 90970 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.0000416

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000446

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00706 AC: 730 AN: 103470 AF XY: 0.00739

Gnomad AFR exome AF: 0.00500

Gnomad AMR exome AF: 0.0101

Gnomad ASJ exome AF: 0.00661

Gnomad EAS exome AF: 0.00635

Gnomad FIN exome AF: 0.00495

Gnomad NFE exome AF: 0.00604

Gnomad OTH exome AF: 0.00811

GnomAD4 exome AF: 0.00400 AC: 4665 AN: 1166606 Hom.: 0 AF XY: 0.00427 AC XY: 2472 AN XY: 579126

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

African (AFR) AF: 0.00411 AC: 105 AN: 25524

American (AMR) AF: 0.00785 AC: 198 AN: 25222

Ashkenazi Jewish (ASJ) AF: 0.00540 AC: 105 AN: 19460

East Asian (EAS) AF: 0.00348 AC: 119 AN: 34212

South Asian (SAS) AF: 0.00837 AC: 486 AN: 58064

European-Finnish (FIN) AF: 0.00512 AC: 198 AN: 38684

Middle Eastern (MID) AF: 0.00322 AC: 15 AN: 4662

European-Non Finnish (NFE) AF: 0.00352 AC: 3210 AN: 912342

Other (OTH) AF: 0.00473 AC: 229 AN: 48436

⚠️ 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: 0.0000330 AC: 3 AN: 90970 Hom.: 0 Cov.: 30 AF XY: 0.0000236 AC XY: 1 AN XY: 42312

African (AFR) AF: 0.0000416 AC: 1 AN: 24066

American (AMR) AF: 0.00 AC: 0 AN: 7944

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 2996

South Asian (SAS) AF: 0.00 AC: 0 AN: 3124

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 3824

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 128

European-Non Finnish (NFE) AF: 0.0000446 AC: 2 AN: 44838

Other (OTH) AF: 0.00 AC: 0 AN: 1186

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

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;