rs794727995

Positions:

• chr1-160314111-C-T

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1 PM2 PP2 PP3 PP5_Very_Strong

The ENST00000241704.8(COPA):​c.721G>A​(p.Glu241Lys) variant causes a missense change involving the alteration of a conserved nucleotide. 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 Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E241A) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: COPA ENST00000241704.8 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 7.47

Genes affected

COPA (HGNC:2230): (COPI coat complex subunit alpha) In eukaryotic cells, protein transport between the endoplasmic reticulum and Golgi compartments is mediated in part by non-clathrin-coated vesicular coat proteins (COPs). Seven coat proteins have been identified, and they represent subunits of a complex known as coatomer. The subunits are designated alpha-COP, beta-COP, beta-prime-COP, gamma-COP, delta-COP, epsilon-COP, and zeta-COP. The alpha-COP, encoded by COPA, shares high sequence similarity with RET1P, the alpha subunit of the coatomer complex in yeast. Also, the N-terminal 25 amino acids of alpha-COP encode the bioactive peptide, xenin, which stimulates exocrine pancreatic secretion and may act as a gastrointestinal hormone. Alternative splicing results in multiple splice forms encoding distinct isoforms. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Pathogenic. Variant got 14 ACMG points.

• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 7 uncertain in ENST00000241704.8
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), COPA. . Gene score misZ 3.558 (greater than the threshold 3.09). Trascript score misZ 4.7888 (greater than threshold 3.09). GenCC has associacion of gene with autoimmune interstitial lung disease-arthritis syndrome.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.793
• PP5: Variant 1-160314111-C-T is Pathogenic according to our data. Variant chr1-160314111-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 199256.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COPA	NM_004371.4	c.721G>A	p.Glu241Lys	missense_variant	9/33	ENST00000241704.8	NP_004362.2
COPA	NM_001098398.2	c.721G>A	p.Glu241Lys	missense_variant	9/33		NP_001091868.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COPA	ENST00000241704.8	c.721G>A	p.Glu241Lys	missense_variant	9/33	1	NM_004371.4	ENSP00000241704	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Autoimmune interstitial lung disease-arthritis syndrome Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	Sep 16, 2022	ACMG classification criteria: PS3 supporting, PS4 supporting, PM2 moderated, PM6 moderated, PP1 strong, PP2 supporting, PP3 supporting -
Pathogenic, criteria provided, single submitter	research	Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine	Apr 20, 2015	Segregates with the phenotype in an affected family, in vitro functional studies. The family showed incomplete penetrance, with unaffected carriers over six generations. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jun 01, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	May 07, 2019	For these reasons, this variant has been classified as Pathogenic. This variant has been reported to affect COPA protein function (PMID: 25894502). This variant has been observed to be de novo in an individual affected with autoimmune interstitial lung, joint, and kidney disease and segregates with disease in several families (PMID: 29137621, 25894502). ClinVar contains an entry for this variant (Variation ID: 199256) This variant is not present in population databases (ExAC no frequency). This sequence change replaces glutamic acid with lysine at codon 241 of the COPA protein (p.Glu241Lys). The glutamic acid residue is highly conserved and there is a small physicochemical difference between glutamic acid and lysine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.36	D
BayesDel_noAF	Pathogenic	0.28
CADD	Pathogenic	32
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.50	.;.;D;.;.
Eigen	Pathogenic	0.72
Eigen_PC	Pathogenic	0.75
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D;D;D;D;D
M_CAP	Uncertain	0.18	D
MetaRNN	Pathogenic	0.79	D;D;D;D;D
MetaSVM	Uncertain	0.093	D
MutationAssessor	Benign	1.8	.;L;L;.;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.88	D
PROVEAN	Uncertain	-3.9	.;D;D;.;.
REVEL	Pathogenic	0.76
Sift	Uncertain	0.0010	.;D;D;.;.
Sift4G	Uncertain	0.0030	.;D;D;.;.
Polyphen		0.99, 1.0	.;D;D;.;.
Vest4		0.94, 0.90
MutPred		0.56		.;Gain of MoRF binding (P = 0.0032);Gain of MoRF binding (P = 0.0032);Gain of MoRF binding (P = 0.0032);Gain of MoRF binding (P = 0.0032);
MVP		0.96
MPC		1.4
ClinPred		1.0	D
GERP RS		5.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.90
gMVP		0.76

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: rs794727995; hg19: chr1-160283901;