1-176043721-T-C

Position:

• chr1-176043721-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_022457.7(COP1):​c.1519A>G​(p.Lys507Glu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: COP1 NM_022457.7 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.69

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 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COP1	NM_022457.7	c.1519A>G	p.Lys507Glu	missense_variant	13/20	ENST00000367669.8	NP_071902.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COP1	ENST00000367669.8	c.1519A>G	p.Lys507Glu	missense_variant	13/20	1	NM_022457.7	ENSP00000356641.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 27

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 06, 2024

The c.1519A>G (p.K507E) alteration is located in exon 13 (coding exon 13) of the RFWD2 gene. This alteration results from a A to G substitution at nucleotide position 1519, causing the lysine (K) at amino acid position 507 to be replaced by a glutamic acid (E). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.86
BayesDel_addAF	Pathogenic	0.22	D
BayesDel_noAF	Uncertain	0.080
CADD	Pathogenic	30
DANN	Uncertain	1.0
DEOGEN2	Benign	0.18	T;T;.
Eigen	Uncertain	0.37
Eigen_PC	Uncertain	0.47
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.95	D;D;D
M_CAP	Benign	0.023	T
MetaRNN	Uncertain	0.54	D;D;D
MetaSVM	Benign	-1.0	T
PrimateAI	Pathogenic	0.86	D
PROVEAN	Benign	-1.9	N;N;N
REVEL	Uncertain	0.34
Sift	Benign	0.27	T;T;T
Sift4G	Benign	0.20	T;T;T
Polyphen		0.98	D;.;P
Vest4		0.76
MutPred		0.36		Loss of ubiquitination at K507 (P = 0.0174);.;.;
MVP		0.67
MPC		1.4
ClinPred		0.86	D
GERP RS		5.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.51
gMVP		0.58

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		Details are displayed if max score is > 0.2

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr1-176012857;