rs143115096

Positions:

• chr1-160294803-C-A
• chr1-160294803-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP2 PP3

The NM_004371.4(COPA):​c.2531G>T​(p.Gly844Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,144 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G844D) has been classified as Likely benign.

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
• Consequence: COPA NM_004371.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.41

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]

COPA (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• 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, 0.751

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COPA	NM_004371.4	c.2531G>T	p.Gly844Val	missense_variant	24/33	ENST00000241704.8	NP_004362.2
COPA	NM_001098398.2	c.2558G>T	p.Gly853Val	missense_variant	24/33		NP_001091868.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COPA	ENST00000241704.8	c.2531G>T	p.Gly844Val	missense_variant	24/33	1	NM_004371.4	ENSP00000241704.7

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152144 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 31

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152144 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74328

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.79
BayesDel_addAF	Pathogenic	0.28	D
BayesDel_noAF	Pathogenic	0.17
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Benign	0.24	.;.;T;.;.
Eigen	Pathogenic	0.96
Eigen_PC	Pathogenic	0.92
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.97	D;D;D;D;D
M_CAP	Benign	0.061	D
MetaRNN	Pathogenic	0.75	D;D;D;D;D
MetaSVM	Benign	-0.37	T
MutationAssessor	Pathogenic	3.2	.;.;M;.;.
PrimateAI	Uncertain	0.75	T
PROVEAN	Pathogenic	-5.3	.;D;D;.;.
REVEL	Uncertain	0.53
Sift	Uncertain	0.027	.;D;D;.;.
Sift4G	Uncertain	0.012	.;D;D;.;.
Polyphen		0.99, 1.0	.;D;D;.;.
Vest4		0.91, 0.92
MutPred		0.61		.;.;Loss of disorder (P = 0.0357);.;Loss of disorder (P = 0.0357);
MVP		0.77
MPC		1.2
ClinPred		1.0	D
GERP RS		5.9
RBP_binding_hub_radar		1.1
RBP_regulation_power_radar		2.9
Varity_R		0.70
gMVP		0.69

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: rs143115096; hg19: chr1-160264593;