Genetic Variant GGA3:p.Ser566Arg (chr17-75239457-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_138619.4(GGA3):c.1698T>A(p.Ser566Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000019 in 1,580,766 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 Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S566N) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000020 ( 0 hom. )

Consequence

GGA3
NM_138619.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.786

Publications

0 publications found

Variant links:

Genes affected

GGA3 (HGNC:17079): (golgi associated, gamma adaptin ear containing, ARF binding protein 3) This gene encodes a member of the Golgi-localized, gamma adaptin ear-containing, ARF-binding (GGA) family. This family includes ubiquitous coat proteins that regulate the trafficking of proteins between the trans-Golgi network and the lysosome. These proteins share an amino-terminal VHS domain which mediates sorting of the mannose 6-phosphate receptors at the trans-Golgi network. They also contain a carboxy-terminal region with homology to the ear domain of gamma-adaptins. Multiple alternatively spliced transcript variants have been identified in this gene. [provided by RefSeq, Feb 2010]

GGA3 links:

Genome browser will be placed here

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=0.096161515).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_138619.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
GGA3	NM_138619.4	MANE Select	c.1698T>A	p.Ser566Arg	missense	Exon 14 of 17	NP_619525.1	Q9NZ52-1
GGA3	NM_014001.5		c.1599T>A	p.Ser533Arg	missense	Exon 13 of 16	NP_054720.1	Q9NZ52-2
GGA3	NM_001172703.3		c.1482T>A	p.Ser494Arg	missense	Exon 14 of 17	NP_001166174.1	Q9NZ52-4

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
GGA3	ENST00000537686.6	TSL:1 MANE Select	c.1698T>A	p.Ser566Arg	missense	Exon 14 of 17	ENSP00000438085.3	Q9NZ52-1
GGA3	ENST00000538886.5	TSL:1	c.1599T>A	p.Ser533Arg	missense	Exon 13 of 16	ENSP00000446421.2	Q9NZ52-2
GGA3	ENST00000621870.4	TSL:1	n.*1657T>A		non_coding_transcript_exon	Exon 15 of 18	ENSP00000479464.1	G3V1K5

Frequencies

GnomAD3 genomes

AF:

0.0000132

AC:

AN:

152030

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000242

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000187

AC:

AN:

213844

AF XY:

0.0000256

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 FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000393

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000196

AC:

AN:

1428736

Hom.:

Cov.:

AF XY:

0.0000239

AC XY:

AN XY:

710632

show subpopulations

African (AFR)

AF:

0.0000322

AC:

AN:

31022

American (AMR)

AF:

0.00

AC:

AN:

32284

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24250

East Asian (EAS)

AF:

0.00

AC:

AN:

39546

South Asian (SAS)

AF:

0.00

AC:

AN:

81116

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52814

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5614

European-Non Finnish (NFE)

AF:

0.0000236

AC:

AN:

1103156

Other (OTH)

AF:

0.0000170

AC:

AN:

58934

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.471

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

AF:

0.0000132

AC:

AN:

152030

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74240

show subpopulations

African (AFR)

AF:

0.0000242

AC:

AN:

41388

American (AMR)

AF:

0.00

AC:

AN:

15268

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3466

East Asian (EAS)

AF:

0.00

AC:

AN:

5182

South Asian (SAS)

AF:

0.00

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10608

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

67982

Other (OTH)

AF:

0.00

AC:

AN:

2088

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.550

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome 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

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000113

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.00000824

AC:

ClinVar

ClinVar submissions as Germline

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.21

BayesDel_addAF

Benign

-0.23

BayesDel_noAF

Benign

-0.45

CADD

Benign

(source)

DANN

Benign

0.79

DEOGEN2

Benign

0.054

Eigen

Benign

-0.89

Eigen_PC

Benign

-0.89

FATHMM_MKL

Benign

0.61

LIST_S2

Benign

0.82

M_CAP

Benign

0.0082

MetaRNN

Benign

0.096

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.3

PhyloP100

0.79

PrimateAI

Benign

0.40

REVEL

Benign

0.037

Sift4G

Benign

0.17

Polyphen

0.062

Vest4

0.26

MutPred

0.22

Loss of phosphorylation at S566 (P = 0.0327)

MVP

0.24

ClinPred

0.045

GERP RS

-1.6

PromoterAI

0.017

Neutral

(source)

Varity_R

0.068

gMVP

0.28

Mutation Taster

=89/11

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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