1-176085856-G-A

Position:

• chr1-176085856-G-A

Variant summary

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

The NM_022457.7(COP1):​c.1061C>T​(p.Ala354Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,455,042 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: COP1 NM_022457.7 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.58

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

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.1061C>T	p.Ala354Val	missense_variant	10/20	ENST00000367669.8	NP_071902.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COP1	ENST00000367669.8	c.1061C>T	p.Ala354Val	missense_variant	10/20	1	NM_022457.7	ENSP00000356641.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1455042 Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0 AN XY: 723748

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.03e-7

Gnomad4 OTH exome AF: 0.00

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

Aug 20, 2024

The c.1061C>T (p.A354V) alteration is located in exon 10 (coding exon 10) of the RFWD2 gene. This alteration results from a C to T substitution at nucleotide position 1061, causing the alanine (A) at amino acid position 354 to be replaced by a valine (V). 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	0.77
BayesDel_addAF	Uncertain	0.030	T
BayesDel_noAF	Benign	-0.19
CADD	Pathogenic	28
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.16	T;T;.
Eigen	Uncertain	0.53
Eigen_PC	Uncertain	0.63
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.97	D;D;D
M_CAP	Benign	0.021	T
MetaRNN	Uncertain	0.49	T;T;T
MetaSVM	Benign	-0.62	T
PrimateAI	Uncertain	0.76	T
PROVEAN	Benign	-1.6	N;N;N
REVEL	Benign	0.16
Sift	Benign	0.10	T;T;T
Sift4G	Benign	0.13	T;T;T
Polyphen		0.99	D;.;D
Vest4		0.59
MutPred		0.41		Gain of loop (P = 0.0312);.;.;
MVP		0.21
MPC		0.88
ClinPred		0.91	D
GERP RS		5.8
Varity_R		0.24
gMVP		0.67

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

Publications

LitVar

Other links and lift over

dbSNP: rs1303904235; hg19: chr1-176054992;