1-160290574-C-T

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 1P and 9B. PP3BP6BS1BS2

The NM_004371.4(COPA):​c.3533G>A​(p.Arg1178His) variant causes a missense change. The variant allele was found at a frequency of 0.0000328 in 1,614,042 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1178C) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000034 ( 0 hom. )

Consequence

COPA
NM_004371.4 missense

Scores

7
8
4

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:1O:1

Conservation

PhyloP100: 7.03
Variant links:
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

PP3
MetaRNN computational evidence supports a deleterious effect, 0.782
BP6
Variant 1-160290574-C-T is Benign according to our data. Variant chr1-160290574-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 1488228.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=1, not_provided=1}.
BS1
Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.0000335 (49/1461890) while in subpopulation MID AF= 0.000173 (1/5766). AF 95% confidence interval is 0.0000228. There are 0 homozygotes in gnomad4_exome. There are 29 alleles in male gnomad4_exome subpopulation. Median coverage is 32. This position pass quality control queck.
BS2
High AC in GnomAdExome4 at 49 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
COPANM_004371.4 linkc.3533G>A p.Arg1178His missense_variant Exon 32 of 33 ENST00000241704.8 NP_004362.2 P53621-1
COPANM_001098398.2 linkc.3560G>A p.Arg1187His missense_variant Exon 32 of 33 NP_001091868.1 P53621-2
LOC107985219XR_001738265.2 linkn.537-683C>T intron_variant Intron 2 of 2

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
COPAENST00000241704.8 linkc.3533G>A p.Arg1178His missense_variant Exon 32 of 33 1 NM_004371.4 ENSP00000241704.7 P53621-1

Frequencies

GnomAD3 genomes
AF:
0.0000263
AC:
4
AN:
152152
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000483
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:
0.0000294
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000557
AC:
14
AN:
251446
Hom.:
0
AF XY:
0.0000662
AC XY:
9
AN XY:
135890
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.0000653
Gnomad FIN exome
AF:
0.0000462
Gnomad NFE exome
AF:
0.0000967
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000335
AC:
49
AN:
1461890
Hom.:
0
Cov.:
32
AF XY:
0.0000399
AC XY:
29
AN XY:
727248
show subpopulations
Gnomad4 AFR exome
AF:
0.0000597
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000580
Gnomad4 FIN exome
AF:
0.0000749
Gnomad4 NFE exome
AF:
0.0000315
Gnomad4 OTH exome
AF:
0.0000331
GnomAD4 genome
AF:
0.0000263
AC:
4
AN:
152152
Hom.:
0
Cov.:
32
AF XY:
0.0000269
AC XY:
2
AN XY:
74320
show subpopulations
Gnomad4 AFR
AF:
0.0000483
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:
0.0000294
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000847
Hom.:
0
Bravo
AF:
0.0000416
TwinsUK
AF:
0.000539
AC:
2
ALSPAC
AF:
0.00
AC:
0
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.000116
AC:
1
ExAC
AF:
0.0000659
AC:
8
EpiCase
AF:
0.0000545
EpiControl
AF:
0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:1Benign:1Other:1
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

Autoimmune interstitial lung disease-arthritis syndrome Benign:1Other:1
Likely benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpSep 06, 2024- -
not provided, no classification providedphenotyping onlyGenomeConnect - Invitae Patient Insights Network-Variant interpreted as Uncertain significance and reported on 03-04-2021 by Lab Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information. -
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsNov 12, 2021The c.3560G>A (p.R1187H) alteration is located in exon 32 (coding exon 32) of the COPA gene. This alteration results from a G to A substitution at nucleotide position 3560, causing the arginine (R) at amino acid position 1187 to be replaced by a histidine (H). 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
0.58
BayesDel_addAF
Benign
-0.097
T
BayesDel_noAF
Benign
-0.17
CADD
Pathogenic
32
DANN
Pathogenic
1.0
DEOGEN2
Benign
0.39
.;.;T;.;.
Eigen
Pathogenic
0.84
Eigen_PC
Pathogenic
0.78
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Uncertain
0.96
D;D;D;D;D
M_CAP
Uncertain
0.089
D
MetaRNN
Pathogenic
0.78
D;D;D;D;D
MetaSVM
Uncertain
-0.099
T
MutationAssessor
Pathogenic
3.4
.;.;M;.;.
PrimateAI
Uncertain
0.67
T
PROVEAN
Uncertain
-4.2
.;D;D;.;.
REVEL
Uncertain
0.46
Sift
Uncertain
0.0070
.;D;D;.;.
Sift4G
Uncertain
0.014
.;D;D;.;.
Polyphen
1.0
.;D;D;.;.
Vest4
0.82, 0.86
MVP
0.81
MPC
1.1
ClinPred
0.92
D
GERP RS
5.1
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.29
gMVP
0.79

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs373521245; hg19: chr1-160260364; API