Genetic Variant COPA:p.Ser895Thr (chr1-160293457-A-T) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_004371.4(COPA):c.2683T>A(p.Ser895Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000694 in 1,440,746 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign 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. S895A) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

COPA
NM_004371.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.01

Publications

0 publications found

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 Gene-Disease associations (from GenCC):

autoimmune interstitial lung disease-arthritis syndrome
Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae)

COPA links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.08145064).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COPA	NM_004371.4 link	c.2683T>A	p.Ser895Thr	missense_variant	Exon 26 of 33	ENST00000241704.8	NP_004362.2	P53621-1
COPA	NM_001098398.2 link	c.2710T>A	p.Ser904Thr	missense_variant	Exon 26 of 33		NP_001091868.1	P53621-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COPA	ENST00000241704.8 link	c.2683T>A	p.Ser895Thr	missense_variant	Exon 26 of 33	1	NM_004371.4	ENSP00000241704.7		P53621-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.94e-7

AC:

AN:

1440746

Hom.:

Cov.:

AF XY:

0.00000140

AC XY:

AN XY:

716506

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31758

American (AMR)

AF:

0.00

AC:

AN:

38002

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25456

East Asian (EAS)

AF:

0.00

AC:

AN:

39558

South Asian (SAS)

AF:

0.00

AC:

AN:

82312

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53008

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5712

European-Non Finnish (NFE)

AF:

9.05e-7

AC:

AN:

1105424

Other (OTH)

AF:

0.00

AC:

AN:

59516

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.575

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.066

BayesDel_addAF

Benign

-0.27

BayesDel_noAF

Benign

-0.62

CADD

Benign

(source)

DANN

Benign

0.24

DEOGEN2

Benign

0.044

.;.;T;.;.

Eigen

Benign

-0.88

Eigen_PC

Benign

-0.78

FATHMM_MKL

Uncertain

0.94

LIST_S2

Benign

0.73

T;T;T;T;T

M_CAP

Benign

0.0097

MetaRNN

Benign

0.081

T;T;T;T;T

MetaSVM

Benign

-0.98

MutationAssessor

Benign

1.2

.;.;L;.;.

PhyloP100

2.0

PrimateAI

Benign

0.34

PROVEAN

Benign

-0.56

.;N;N;.;.

REVEL

Benign

0.027

Sift

Benign

0.65

.;T;T;.;.

Sift4G

Benign

0.58

.;T;T;.;.

Polyphen

0.0010, 0.0050

.;B;B;.;.

Vest4

0.27, 0.24

MutPred

0.38

.;.;Gain of glycosylation at S895 (P = 0.0787);.;Gain of glycosylation at S895 (P = 0.0787);

MVP

0.33

MPC

0.46

ClinPred

0.11

GERP RS

1.2

Varity_R

0.027

gMVP

0.39

Mutation Taster

=98/2

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over