Genetic Variant COPA:p.Thr99Thr (chr1-160335254-C-T) – ACMG Classification: Benign (-21 pts)

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_004371.4(COPA):c.297G>A(p.Thr99Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00162 in 1,608,976 control chromosomes in the GnomAD database, including 35 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0018 ( 3 hom., cov: 31)

Exomes 𝑓: 0.0016 ( 32 hom. )

Consequence

COPA
NM_004371.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -1.46

Publications

4 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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.57).

BP6

Variant 1-160335254-C-T is Benign according to our data. Variant chr1-160335254-C-T is described in ClinVar as Benign. ClinVar VariationId is 476027.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-1.46 with no splicing effect.

BS1

Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.00177 (270/152176) while in subpopulation EAS AF = 0.0243 (126/5184). AF 95% confidence interval is 0.0209. There are 3 homozygotes in GnomAd4. There are 139 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.

BS2

High AC in GnomAd4 at 270 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004371.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COPA	NM_004371.4	MANE Select	c.297G>A	p.Thr99Thr	synonymous	Exon 4 of 33	NP_004362.2	P53621-1
	COPA	NM_001098398.2		c.297G>A	p.Thr99Thr	synonymous	Exon 4 of 33	NP_001091868.1	P53621-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
COPA	ENST00000241704.8	TSL:1 MANE Select	c.297G>A	p.Thr99Thr	synonymous	Exon 4 of 33	ENSP00000241704.7	P53621-1
COPA	ENST00000368069.7	TSL:1	c.297G>A	p.Thr99Thr	synonymous	Exon 4 of 33	ENSP00000357048.3	P53621-2
COPA	ENST00000971419.1		c.223G>A	p.Val75Ile	missense	Exon 3 of 30	ENSP00000641478.1

Frequencies

GnomAD3 genomes

AF:

0.00178

AC:

270

AN:

152058

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000990

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00498

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.0246

Gnomad SAS

AF:

0.00249

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000132

Gnomad OTH

AF:

0.00191

GnomAD2 exomes

AF:

0.00468

AC:

1153

AN:

246582

AF XY:

0.00371

show subpopulations

Gnomad AFR exome

AF:

0.000818

Gnomad AMR exome

AF:

0.0210

Gnomad ASJ exome

AF:

0.000100

Gnomad EAS exome

AF:

0.0207

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000117

Gnomad OTH exome

AF:

0.00333

GnomAD4 exome

AF:

0.00160

AC:

2330

AN:

1456800

Hom.:

Cov.:

AF XY:

0.00144

AC XY:

1043

AN XY:

724506

show subpopulations

African (AFR)

AF:

0.000391

AC:

AN:

33250

American (AMR)

AF:

0.0188

AC:

831

AN:

44282

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25982

East Asian (EAS)

AF:

0.0331

AC:

1304

AN:

39354

South Asian (SAS)

AF:

0.000516

AC:

AN:

85304

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53248

Middle Eastern (MID)

AF:

0.000174

AC:

AN:

5758

European-Non Finnish (NFE)

AF:

0.0000568

AC:

AN:

1109522

Other (OTH)

AF:

0.00123

AC:

AN:

60100

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.480

Heterozygous variant carriers

195

293

390

488

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

114

152

190

<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

AF:

0.00177

AC:

270

AN:

152176

Hom.:

Cov.:

AF XY:

0.00187

AC XY:

139

AN XY:

74404

show subpopulations

African (AFR)

AF:

0.000987

AC:

AN:

41528

American (AMR)

AF:

0.00498

AC:

AN:

15274

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.0243

AC:

126

AN:

5184

South Asian (SAS)

AF:

0.00229

AC:

AN:

4814

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10588

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000132

AC:

AN:

68002

Other (OTH)

AF:

0.00331

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

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

Alfa

AF:

0.000334

Hom.:

Bravo

AF:

0.00288

Asia WGS

AF:

0.0110

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Autoimmune interstitial lung disease-arthritis syndrome (1)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.065

BayesDel_noAF

Benign

-0.57

CADD

Benign

0.34

(source)

DANN

Benign

0.80

PhyloP100

-1.5

Mutation Taster

=100/0

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over