Genetic Variant GGA3:p.Ala547Thr (chr17-75239516-C-T) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_138619.4(GGA3):c.1639G>A(p.Ala547Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000704 in 1,419,680 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/23 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 7.0e-7 ( 0 hom. )

Consequence

GGA3
NM_138619.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.48

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:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

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.1639G>A	p.Ala547Thr	missense	Exon 14 of 17	NP_619525.1	Q9NZ52-1
GGA3	NM_014001.5		c.1540G>A	p.Ala514Thr	missense	Exon 13 of 16	NP_054720.1	Q9NZ52-2
GGA3	NM_001172703.3		c.1423G>A	p.Ala475Thr	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.1639G>A	p.Ala547Thr	missense	Exon 14 of 17	ENSP00000438085.3	Q9NZ52-1
GGA3	ENST00000538886.5	TSL:1	c.1540G>A	p.Ala514Thr	missense	Exon 13 of 16	ENSP00000446421.2	Q9NZ52-2
GGA3	ENST00000621870.4	TSL:1	n.*1598G>A		non_coding_transcript_exon	Exon 15 of 18	ENSP00000479464.1	G3V1K5

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00

AC:

AN:

180552

AF XY:

0.00

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:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

7.04e-7

AC:

AN:

1419680

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

704494

show subpopulations

African (AFR)

AF:

0.0000316

AC:

AN:

31634

American (AMR)

AF:

0.00

AC:

AN:

33958

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24794

East Asian (EAS)

AF:

0.00

AC:

AN:

38104

South Asian (SAS)

AF:

0.00

AC:

AN:

81668

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51036

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5626

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1094236

Other (OTH)

AF:

0.00

AC:

AN:

58624

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.625

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.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

ClinVar submissions

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

0.065

BayesDel_addAF

Benign

-0.17

BayesDel_noAF

Benign

-0.48

CADD

Benign

(source)

DANN

Benign

0.86

DEOGEN2

Benign

0.026

Eigen

Benign

-0.42

Eigen_PC

Benign

-0.45

FATHMM_MKL

Benign

0.63

LIST_S2

Benign

0.81

M_CAP

Benign

0.0094

MetaRNN

Benign

0.098

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.7

PhyloP100

1.5

PrimateAI

Benign

0.33

REVEL

Benign

0.041

Sift4G

Benign

0.26

Polyphen

0.76

Vest4

0.10

MutPred

0.19

Gain of glycosylation at A547 (P = 0.0011)

MVP

0.43

ClinPred

0.15

GERP RS

3.0

PromoterAI

0.0033

Neutral

(source)

Varity_R

0.080

gMVP

0.34

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.33

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.33

Position offset: -5

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over