chr1-160293457-A-C

Position:

chr1-160293457-A-C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 1P and 13B. PP2BP4_StrongBP6BS1BS2

The NM_004371.4(COPA):c.2683T>G(p.Ser895Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000584 in 1,592,658 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign 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. S895F) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00030 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000033 ( 0 hom. )

Consequence

COPA
NM_004371.4 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 2.01

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]

COPA links:

COPA (HGNC:):

COPA links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -12 ACMG points.

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.

BP4

Computational evidence support a benign effect (MetaRNN=0.008788705).

BP6

Variant 1-160293457-A-C is Benign according to our data. Variant chr1-160293457-A-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 542649.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.000296 (45/151912) while in subpopulation AFR AF= 0.00109 (45/41398). AF 95% confidence interval is 0.000835. There are 0 homozygotes in gnomad4. There are 19 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High AC in GnomAd4 at 45 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COPA	NM_004371.4 linkuse as main transcript	c.2683T>G	p.Ser895Ala	missense_variant	26/33	ENST00000241704.8	NP_004362.2	P53621-1
COPA	NM_001098398.2 linkuse as main transcript	c.2710T>G	p.Ser904Ala	missense_variant	26/33		NP_001091868.1	P53621-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COPA	ENST00000241704.8 linkuse as main transcript	c.2683T>G	p.Ser895Ala	missense_variant	26/33	1	NM_004371.4	ENSP00000241704.7		P53621-1

Frequencies

GnomAD3 genomes

AF:

0.000296

AC:

AN:

151808

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00109

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

GnomAD3 exomes

AF:

0.000116

AC:

AN:

224572

Hom.:

AF XY:

0.0000740

AC XY:

AN XY:

121702

show subpopulations

Gnomad AFR exome

AF:

0.00155

Gnomad AMR exome

AF:

0.0000361

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000192

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000333

AC:

AN:

1440746

Hom.:

Cov.:

AF XY:

0.0000349

AC XY:

AN XY:

716506

show subpopulations

Gnomad4 AFR exome

AF:

0.00104

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000486

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000452

Gnomad4 OTH exome

AF:

0.000101

GnomAD4 genome

AF:

0.000296

AC:

AN:

151912

Hom.:

Cov.:

AF XY:

0.000256

AC XY:

AN XY:

74254

show subpopulations

Gnomad4 AFR

AF:

0.00109

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

Alfa

AF:

0.000232

Hom.:

Bravo

AF:

0.000382

ESP6500AA

AF:

0.00159

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000157

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 26, 2022

The c.2710T>G (p.S904A) alteration is located in exon 26 (coding exon 26) of the COPA gene. This alteration results from a T to G substitution at nucleotide position 2710, causing the serine (S) at amino acid position 904 to be replaced by an alanine (A). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Autoimmune interstitial lung disease-arthritis syndrome

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

May 15, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.063

BayesDel_addAF

Benign

-0.61

BayesDel_noAF

Benign

-0.67

CADD

Benign

DANN

Benign

0.30

DEOGEN2

Benign

0.034

.;.;T;.;.

Eigen

Benign

-1.0

Eigen_PC

Benign

-0.88

FATHMM_MKL

Uncertain

0.89

LIST_S2

Benign

0.47

T;T;T;T;T

M_CAP

Benign

0.0065

MetaRNN

Benign

0.0088

T;T;T;T;T

MetaSVM

Benign

-0.95

MutationAssessor

Benign

-0.15

.;.;N;.;.

PrimateAI

Benign

0.33

PROVEAN

Benign

0.11

.;N;N;.;.

REVEL

Benign

0.023

Sift

Benign

0.73

.;T;T;.;.

Sift4G

Benign

0.81

.;T;T;.;.

Polyphen

0.0

.;B;B;.;.

Vest4

0.20, 0.16

MVP

0.23

MPC

0.42

ClinPred

0.0021

GERP RS

1.2

RBP_binding_hub_radar

1.0

RBP_regulation_power_radar

2.3

Varity_R

0.022

gMVP

0.30

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over