12-54340563-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_016057.3(COPZ1):c.35C>T(p.Thr12Ile) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: COPZ1 NM_016057.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.04

Genes affected

COPZ1 (HGNC:2243): (COPI coat complex subunit zeta 1) This gene encodes a subunit of the cytoplasmic coatamer protein complex, which is involved in autophagy and intracellular protein trafficking. The coatomer protein complex is comprised of seven subunits and functions as the coat protein of coat protein complex (COP)I-vesicles. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Nov 2012]

(HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.802

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COPZ1	NM_016057.3	c.35C>T	p.Thr12Ile	missense_variant	2/9	ENST00000262061.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COPZ1	ENST00000262061.7	c.35C>T	p.Thr12Ile	missense_variant	2/9	1	NM_016057.3	P1
	ENST00000553061.1	n.546-4499C>T		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

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

Nov 18, 2023

The c.35C>T (p.T12I) alteration is located in exon 2 (coding exon 2) of the COPZ1 gene. This alteration results from a C to T substitution at nucleotide position 35, causing the threonine (T) at amino acid position 12 to be replaced by an isoleucine (I). 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	Uncertain	0.52
BayesDel_addAF	Pathogenic	0.44	D
BayesDel_noAF	Pathogenic	0.40
Cadd	Pathogenic	27
Dann	Uncertain	1.0
DEOGEN2	Benign	0.13	T;T;.;T;.;T;.;T
Eigen	Uncertain	0.57
Eigen_PC	Uncertain	0.60
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.91	D;D;D;D;D;D;D;D
M_CAP	Benign	0.018	T
MetaRNN	Pathogenic	0.80	D;D;D;D;D;D;D;D
MetaSVM	Benign	-0.40	T
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D;D
PrimateAI	Pathogenic	0.80	D
PROVEAN	Pathogenic	-4.4	D;D;D;D;D;D;D;D
REVEL	Uncertain	0.39
Sift	Benign	0.032	D;T;T;T;T;D;T;D
Sift4G	Uncertain	0.034	D;T;T;D;T;T;T;D
Polyphen		1.0	.;D;.;.;.;.;.;.
Vest4		0.93, 0.90, 0.89, 0.92, 0.93
MutPred		0.50		Gain of catalytic residue at L10 (P = 0.001);Gain of catalytic residue at L10 (P = 0.001);.;Gain of catalytic residue at L10 (P = 0.001);Gain of catalytic residue at L10 (P = 0.001);Gain of catalytic residue at L10 (P = 0.001);Gain of catalytic residue at L10 (P = 0.001);.;
MVP		0.80
MPC		0.59
ClinPred		0.99	D
GERP RS		4.8
Varity_R		0.50
gMVP		0.75

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: chr12-54734347;