dbSNP rs1217492840: GGA3:p.Lys687Arg (chr17-75238653-T-C) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2PP3

The NM_138619.4(GGA3):c.2060A>G(p.Lys687Arg) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 2/3 splice prediction tools predicting alterations to normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K687T) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 31)

Consequence

GGA3
NM_138619.4 missense, splice_region

Scores

Splicing: ADA: 0.9982

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 8.02

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 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. Scorers claiming Uncertain: max_spliceai. No scorers claiming Benign.

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.2060A>G	p.Lys687Arg	missense splice_region	Exon 16 of 17	NP_619525.1	Q9NZ52-1
GGA3	NM_014001.5		c.1961A>G	p.Lys654Arg	missense splice_region	Exon 15 of 16	NP_054720.1	Q9NZ52-2
GGA3	NM_001172703.3		c.1844A>G	p.Lys615Arg	missense splice_region	Exon 16 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.2060A>G	p.Lys687Arg	missense splice_region	Exon 16 of 17	ENSP00000438085.3	Q9NZ52-1
GGA3	ENST00000538886.5	TSL:1	c.1961A>G	p.Lys654Arg	missense splice_region	Exon 15 of 16	ENSP00000446421.2	Q9NZ52-2
GGA3	ENST00000621870.4	TSL:1	n.*2019A>G		splice_region non_coding_transcript_exon	Exon 17 of 18	ENSP00000479464.1	G3V1K5

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.079

BayesDel_addAF

Uncertain

0.098

BayesDel_noAF

Benign

-0.10

CADD

Pathogenic

(source)

DANN

Benign

0.97

DEOGEN2

Benign

0.11

Eigen

Uncertain

0.67

Eigen_PC

Uncertain

0.65

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.95

M_CAP

Benign

0.011

MetaRNN

Uncertain

0.71

MetaSVM

Benign

-0.78

MutationAssessor

Uncertain

2.6

PhyloP100

8.0

PrimateAI

Uncertain

0.63

REVEL

Benign

0.25

Sift4G

Uncertain

0.0080

Polyphen

1.0

Vest4

0.61

MutPred

0.60

Gain of solvent accessibility (P = 0.0503)

MVP

0.82

ClinPred

0.97

GERP RS

5.2

PromoterAI

-0.15

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.54

gMVP

0.51

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.96

SpliceAI score (max)

0.25

Details are displayed if max score is > 0.2

DS_DL_spliceai

0.25

Position offset: -1

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over