Genetic Variant COPG1:p.Ala196Thr (chr3-129257476-G-A) – ACMG Classification: Likely_pathogenic (6 pts)

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_Strong

The NM_016128.4(COPG1):c.586G>A(p.Ala196Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,880 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 Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000027 ( 0 hom. )

Consequence

COPG1
NM_016128.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 9.54

Variant links:

Genes affected

COPG1 (HGNC:2236): (COPI coat complex subunit gamma 1) Predicted to enable structural molecule activity. Predicted to be involved in several processes, including Golgi vesicle transport; establishment of Golgi localization; and organelle transport along microtubule. Located in Golgi apparatus. [provided by Alliance of Genome Resources, Apr 2022]

COPG1 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.966

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COPG1	NM_016128.4 link	c.586G>A	p.Ala196Thr	missense_variant	Exon 9 of 24	ENST00000314797.10	NP_057212.1	Q9Y678

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COPG1	ENST00000314797.10 link	c.586G>A	p.Ala196Thr	missense_variant	Exon 9 of 24	1	NM_016128.4	ENSP00000325002.6		Q9Y678
COPG1	ENST00000515725.5 link	n.845G>A		non_coding_transcript_exon_variant	Exon 8 of 23	2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

251374

Hom.:

AF XY:

0.00000736

AC XY:

AN XY:

135846

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.0000992

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000274

AC:

AN:

1461880

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

727242

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.0000765

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000187

Gnomad4 NFE exome

AF:

8.99e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000468

Hom.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Dec 30, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.586G>A (p.A196T) alteration is located in exon 9 (coding exon 9) of the COPG1 gene. This alteration results from a G to A substitution at nucleotide position 586, causing the alanine (A) at amino acid position 196 to be replaced by a threonine (T). 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

0.99

BayesDel_addAF

Pathogenic

0.29

BayesDel_noAF

Pathogenic

0.18

CADD

Uncertain

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.36

Eigen

Pathogenic

0.80

Eigen_PC

Pathogenic

0.70

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Pathogenic

0.98

M_CAP

Uncertain

0.12

MetaRNN

Pathogenic

0.97

MetaSVM

Uncertain

-0.17

MutationAssessor

Pathogenic

3.2

PrimateAI

Pathogenic

0.83

PROVEAN

Uncertain

-3.2

REVEL

Uncertain

0.57

Sift

Uncertain

0.0010

Sift4G

Uncertain

0.010

Polyphen

1.0

Vest4

0.89

MutPred

0.84

Loss of MoRF binding (P = 0.1188);

MVP

0.72

MPC

1.1

ClinPred

0.97

GERP RS

5.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.8

Varity_R

0.31

gMVP

0.71

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.

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