Genetic Variant NM_013365.5:c.913G>A (chr22-37625049-G-A) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_013365.5(GGA1):c.913G>A(p.Gly305Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00001 in 1,599,572 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000097 ( 0 hom. )

Consequence

GGA1
NM_013365.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 9.68

Variant links:

Genes affected

GGA1 (HGNC:17842): (golgi associated, gamma adaptin ear containing, ARF binding protein 1) This gene encodes a member of the Golgi-localized, gamma adaptin ear-containing, ARF-binding (GGA) protein family. Members of this family are 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 encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

GGA1 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.28386447).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GGA1	NM_013365.5 link	c.913G>A	p.Gly305Ser	missense_variant	Exon 10 of 17	ENST00000343632.9	NP_037497.1	Q9UJY5-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GGA1	ENST00000343632.9 link	c.913G>A	p.Gly305Ser	missense_variant	Exon 10 of 17	1	NM_013365.5	ENSP00000341344.4		Q9UJY5-1
GGA1	ENST00000381756.9 link	c.964G>A	p.Gly322Ser	missense_variant	Exon 10 of 17	1		ENSP00000371175.5		Q9UJY5-6

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152222

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000177

AC:

AN:

225768

Hom.:

AF XY:

0.0000246

AC XY:

AN XY:

122118

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000622

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000360

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000995

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000967

AC:

AN:

1447232

Hom.:

Cov.:

AF XY:

0.0000111

AC XY:

AN XY:

718678

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000465

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000477

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000723

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152340

Hom.:

Cov.:

AF XY:

0.0000268

AC XY:

AN XY:

74494

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000653

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000313

Hom.:

Bravo

AF:

0.00000378

ExAC

AF:

0.00000825

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Dec 15, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.913G>A (p.G305S) alteration is located in exon 10 (coding exon 10) of the GGA1 gene. This alteration results from a G to A substitution at nucleotide position 913, causing the glycine (G) at amino acid position 305 to be replaced by a serine (S). 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

Benign

0.15

BayesDel_addAF

Uncertain

0.064

BayesDel_noAF

Benign

-0.15

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.37

T;.;.

Eigen

Uncertain

0.40

Eigen_PC

Uncertain

0.40

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.93

D;D;D

M_CAP

Benign

0.040

MetaRNN

Benign

0.28

T;T;T

MetaSVM

Benign

-0.82

MutationAssessor

Uncertain

2.6

M;.;.

PrimateAI

Uncertain

0.61

PROVEAN

Uncertain

-3.8

D;D;D

REVEL

Benign

0.28

Sift

Benign

0.078

T;D;D

Sift4G

Uncertain

0.025

D;D;D

Polyphen

0.66

P;.;.

Vest4

0.50

MutPred

0.54

.;Loss of helix (P = 0.028);.;

MVP

0.58

MPC

0.91

ClinPred

0.90

GERP RS

5.0

Varity_R

0.25

gMVP

0.39

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.10

Details are displayed if max score is > 0.2

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over