Genetic Variant GGA3:p.Ala512Thr (chr17-75239838-C-T) – ACMG Classification: Benign (-10 pts)

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_StrongBP6_ModerateBS2

The NM_138619.4(GGA3):c.1534G>A(p.Ala512Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000496 in 1,613,954 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.00058 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00049 ( 9 hom. )

Consequence

GGA3
NM_138619.4 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: -0.842

Publications

3 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:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -10 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.002592057).

BP6

Variant 17-75239838-C-T is Benign according to our data. Variant chr17-75239838-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 2229758.Status of the report is criteria_provided_single_submitter, 1 stars.

BS2

High Homozygotes in GnomAdExome4 at 9 AR gene

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.1534G>A	p.Ala512Thr	missense	Exon 13 of 17	NP_619525.1	Q9NZ52-1
GGA3	NM_014001.5		c.1435G>A	p.Ala479Thr	missense	Exon 12 of 16	NP_054720.1	Q9NZ52-2
GGA3	NM_001172703.3		c.1318G>A	p.Ala440Thr	missense	Exon 13 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.1534G>A	p.Ala512Thr	missense	Exon 13 of 17	ENSP00000438085.3	Q9NZ52-1
GGA3	ENST00000538886.5	TSL:1	c.1435G>A	p.Ala479Thr	missense	Exon 12 of 16	ENSP00000446421.2	Q9NZ52-2
GGA3	ENST00000621870.4	TSL:1	n.*1493G>A		non_coding_transcript_exon	Exon 14 of 18	ENSP00000479464.1	G3V1K5

Frequencies

GnomAD3 genomes

AF:

0.000585

AC:

AN:

152210

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000262

Gnomad ASJ

AF:

0.0190

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000235

Gnomad OTH

AF:

0.00143

GnomAD2 exomes

AF:

0.000815

AC:

204

AN:

250242

AF XY:

0.000819

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000318

Gnomad ASJ exome

AF:

0.0170

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000924

Gnomad NFE exome

AF:

0.000106

Gnomad OTH exome

AF:

0.00114

GnomAD4 exome

AF:

0.000486

AC:

711

AN:

1461626

Hom.:

Cov.:

AF XY:

0.000521

AC XY:

379

AN XY:

727132

show subpopulations

African (AFR)

AF:

0.0000299

AC:

AN:

33480

American (AMR)

AF:

0.000201

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0184

AC:

482

AN:

26136

East Asian (EAS)

AF:

0.000126

AC:

AN:

39700

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.0000564

AC:

AN:

53162

Middle Eastern (MID)

AF:

0.000347

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000113

AC:

126

AN:

1112002

Other (OTH)

AF:

0.00136

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.472

Heterozygous variant carriers

136

181

226

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

<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:

0.000584

AC:

AN:

152328

Hom.:

Cov.:

AF XY:

0.000524

AC XY:

AN XY:

74494

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41570

American (AMR)

AF:

0.000261

AC:

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.0190

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5186

South Asian (SAS)

AF:

0.00

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000235

AC:

AN:

68024

Other (OTH)

AF:

0.00142

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.513

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:

0.000917

Hom.:

Bravo

AF:

0.000570

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000814

AC:

ExAC

AF:

0.000577

AC:

EpiCase

AF:

0.000327

EpiControl

AF:

0.000296

ClinVar

ClinVar submissions as Germline

Significance:Likely benign

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

0.057

BayesDel_addAF

Benign

-0.57

BayesDel_noAF

Benign

-0.76

CADD

Benign

0.12

(source)

DANN

Benign

0.46

DEOGEN2

Benign

0.021

Eigen

Benign

-1.9

Eigen_PC

Benign

-1.9

FATHMM_MKL

Benign

0.030

LIST_S2

Benign

0.16

M_CAP

Benign

0.0048

MetaRNN

Benign

0.0026

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-0.57

PhyloP100

-0.84

PrimateAI

Benign

0.24

PROVEAN

Benign

-1.6

REVEL

Benign

0.0080

Sift

Benign

0.042

Sift4G

Benign

0.72

Polyphen

0.0

Vest4

0.062

MVP

0.25

ClinPred

0.014

GERP RS

-9.0

Varity_R

0.071

gMVP

0.30

Mutation Taster

=99/1

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over