chr1-175989442-T-G

Variant names:

• chr1-175989442-T-G
• rs111531372
• NM_022457.7:c.1767A>C

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_022457.7(COP1):​c.1767A>C​(p.Lys589Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. K589K) has been classified as Benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: COP1 NM_022457.7 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.250
• Publications: 0 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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3053279).

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.1767A>C	p.Lys589Asn	missense	Exon 16 of 20	NP_071902.2
	COP1	NM_001001740.4		c.1695A>C	p.Lys565Asn	missense	Exon 15 of 19	NP_001001740.1	Q8NHY2-2
	COP1	NM_001286644.2		c.1047A>C	p.Lys349Asn	missense	Exon 14 of 18	NP_001273573.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COP1	ENST00000367669.8	TSL:1 MANE Select	c.1767A>C	p.Lys589Asn	missense	Exon 16 of 20	ENSP00000356641.3	Q8NHY2-1
	COP1	ENST00000308769.12	TSL:1	c.1695A>C	p.Lys565Asn	missense	Exon 15 of 19	ENSP00000310943.8	Q8NHY2-2
	COP1	ENST00000367667.5	TSL:1	n.*943A>C		non_coding_transcript_exon	Exon 14 of 18	ENSP00000356639.1	H0Y340

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 27

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Benign	0.20	T
Eigen	Benign	0.12
Eigen_PC	Benign	0.087
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.31	T
MetaSVM	Benign	-0.95	T
PhyloP100		0.25
PrimateAI	Pathogenic	0.83	D
PROVEAN	Benign	-2.2	N
REVEL	Benign	0.14
Sift	Benign	0.033	D
Sift4G	Uncertain	0.044	D
Polyphen		0.99	D
Vest4		0.69
MutPred		0.47		Loss of methylation at K589 (P = 0.0122)
MVP		0.37
MPC		1.3
ClinPred		0.80	D
GERP RS		0.93
Varity_R		0.62
gMVP		0.50
Mutation Taster		=47/53	disease causing

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: rs111531372; hg19: chr1-175958578;