Variant 16-23470025-C-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_015044.4(GGA2):c.1591G>T(p.Asp531Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000007 in 1,428,412 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: 7.0e-7 ( 0 hom. )

Consequence

GGA2
NM_015044.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.77

Variant links:

Genes affected

GGA2 (HGNC:16064): (golgi associated, gamma adaptin ear containing, ARF binding protein 2) 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. This family member may play a significant role in cargo molecules regulation and clathrin-coated vesicle assembly. [provided by RefSeq, Jul 2008]

GGA2 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.846

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
GGA2	NM_015044.4 linkuse as main transcript	c.1591G>T	p.Asp531Tyr	missense_variant	15/17	ENST00000309859.8
GGA2	XM_047433801.1 linkuse as main transcript	c.1561G>T	p.Asp521Tyr	missense_variant	16/18
GGA2	XM_047433802.1 linkuse as main transcript	c.1480G>T	p.Asp494Tyr	missense_variant	15/17

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GGA2	ENST00000309859.8 linkuse as main transcript	c.1591G>T	p.Asp531Tyr	missense_variant	15/17	1	NM_015044.4	P1
GGA2	ENST00000567468.5 linkuse as main transcript	c.625-4627G>T		intron_variant		2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.00e-7

AC:

AN:

1428412

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

708676

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

9.13e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 06, 2023

The c.1591G>T (p.D531Y) alteration is located in exon 15 (coding exon 15) of the GGA2 gene. This alteration results from a G to T substitution at nucleotide position 1591, causing the aspartic acid (D) at amino acid position 531 to be replaced by a tyrosine (Y). 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

Uncertain

0.53

BayesDel_addAF

Uncertain

0.093

BayesDel_noAF

Benign

-0.10

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.50

Eigen

Uncertain

0.67

Eigen_PC

Uncertain

0.64

FATHMM_MKL

Uncertain

0.81

LIST_S2

Uncertain

0.96

M_CAP

Benign

0.029

MetaRNN

Pathogenic

0.85

MetaSVM

Benign

-0.72

MutationAssessor

Uncertain

2.1

MutationTaster

Benign

0.97

D;D

PrimateAI

Uncertain

0.57

PROVEAN

Uncertain

-3.8

REVEL

Uncertain

0.32

Sift

Uncertain

0.0050

Sift4G

Uncertain

0.0080

Polyphen

1.0

Vest4

0.75

MutPred

0.67

Loss of disorder (P = 0.0617);

MVP

0.61

MPC

0.65

ClinPred

0.98

GERP RS

5.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.44

gMVP

0.69

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over