Genetic Variant COP1:c.1142-18_1142-8dupTTTTTTTTTTT (chr1-176081294-G-GAAAAAAAAAAA) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

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

The NM_022457.7(COP1):c.1142-18_1142-8dupTTTTTTTTTTT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000234 in 1,283,920 control chromosomes in the GnomAD database, with no homozygous occurrence. It is difficult to determine the true allele frequency of this variant because it is of type INS_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.000022 ( 0 hom., cov: 30)

Exomes 𝑓: 8.4e-7 ( 0 hom. )

Consequence

COP1
NM_022457.7 splice_region, intron

Scores

Not classified

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.493

Publications

1 publications found

Variant links:

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]

COP1 links:

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ACMG classification

Classification was made for transcript

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

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
COP1	NM_022457.7	MANE Select	c.1142-18_1142-8dupTTTTTTTTTTT	splice_region intron	N/A	NP_071902.2
COP1	NM_001001740.4		c.1070-18_1070-8dupTTTTTTTTTTT	splice_region intron	N/A	NP_001001740.1	Q8NHY2-2
COP1	NM_001286644.2		c.422-18_422-8dupTTTTTTTTTTT	splice_region intron	N/A	NP_001273573.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
COP1	ENST00000367669.8	TSL:1 MANE Select	c.1142-8_1142-7insTTTTTTTTTTT	splice_region intron	N/A	ENSP00000356641.3	Q8NHY2-1
COP1	ENST00000308769.12	TSL:1	c.1070-8_1070-7insTTTTTTTTTTT	splice_region intron	N/A	ENSP00000310943.8	Q8NHY2-2
COP1	ENST00000367667.5	TSL:1	n.318-8_318-7insTTTTTTTTTTT	splice_region intron	N/A	ENSP00000356639.1	H0Y340

Frequencies

GnomAD3 genomes

AF:

0.0000220

AC:

AN:

90988

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000415

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:

0.0000223

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

8.38e-7

AC:

AN:

1192932

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

592366

show subpopulations

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

African (AFR)

AF:

0.00

AC:

AN:

26132

American (AMR)

AF:

0.00

AC:

AN:

25848

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19960

East Asian (EAS)

AF:

0.00

AC:

AN:

34966

South Asian (SAS)

AF:

0.00

AC:

AN:

59702

European-Finnish (FIN)

AF:

0.00

AC:

AN:

39570

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4754

European-Non Finnish (NFE)

AF:

0.00000107

AC:

AN:

932374

Other (OTH)

AF:

0.00

AC:

AN:

49626

⚠️ 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.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.375

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0000220

AC:

AN:

90988

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

42324

show subpopulations

African (AFR)

AF:

0.0000415

AC:

AN:

24072

American (AMR)

AF:

0.00

AC:

AN:

7944

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2386

East Asian (EAS)

AF:

0.00

AC:

AN:

2996

South Asian (SAS)

AF:

0.00

AC:

AN:

3124

European-Finnish (FIN)

AF:

0.00

AC:

AN:

3826

Middle Eastern (MID)

AF:

0.00

AC:

AN:

128

European-Non Finnish (NFE)

AF:

0.0000223

AC:

AN:

44848

Other (OTH)

AF:

0.00

AC:

AN:

1186

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.375

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

0.49

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over