Variant chr22-37621616-A-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_013365.5(GGA1):c.529A>C(p.Met177Leu) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000222 in 1,398,416 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/23 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.000022 ( 0 hom. )

Consequence

GGA1
NM_013365.5 missense, splice_region

Scores

Splicing: ADA: 0.0001963

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.44

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:

GGA1 (HGNC:):

GGA1 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.06662089).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GGA1	NM_013365.5 linkuse as main transcript	c.529A>C	p.Met177Leu	missense_variant, splice_region_variant	7/17	ENST00000343632.9	NP_037497.1	Q9UJY5-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GGA1	ENST00000343632.9 linkuse as main transcript	c.529A>C	p.Met177Leu	missense_variant, splice_region_variant	7/17	1	NM_013365.5	ENSP00000341344.4		Q9UJY5-1
GGA1	ENST00000381756.9 linkuse as main transcript	c.580A>C	p.Met194Leu	missense_variant, splice_region_variant	7/17	1		ENSP00000371175.5		Q9UJY5-6

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000635

AC:

AN:

157544

Hom.:

AF XY:

0.0000121

AC XY:

AN XY:

82952

show subpopulations

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 SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000164

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000222

AC:

AN:

1398416

Hom.:

Cov.:

AF XY:

0.0000203

AC XY:

AN XY:

689928

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:

0.0000278

Gnomad4 OTH exome

AF:

0.0000172

GnomAD4 genome

Cov.:

Bravo

AF:

0.0000189

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000121

AC:

ExAC

AF:

0.0000100

AC:

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

Oct 08, 2024

The c.529A>C (p.M177L) alteration is located in exon 7 (coding exon 7) of the GGA1 gene. This alteration results from a A to C substitution at nucleotide position 529, causing the methionine (M) at amino acid position 177 to be replaced by a leucine (L). 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

Benign

-0.12

BayesDel_noAF

Benign

-0.40

CADD

Benign

DANN

Benign

0.73

DEOGEN2

Benign

0.096

T;.;T;.;.;.;T;T

Eigen

Benign

-0.27

Eigen_PC

Benign

-0.081

FATHMM_MKL

Uncertain

0.96

LIST_S2

Benign

0.66

T;T;.;T;T;T;.;T

M_CAP

Benign

0.0063

MetaRNN

Benign

0.067

T;T;T;T;T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.17

N;.;.;N;.;.;.;.

PrimateAI

Uncertain

0.65

PROVEAN

Benign

-0.26

N;N;N;N;N;N;N;N

REVEL

Benign

0.051

Sift

Benign

1.0

T;T;T;T;T;T;T;T

Sift4G

Benign

1.0

T;T;T;T;T;T;T;T

Polyphen

0.0

B;.;.;.;.;.;.;.

Vest4

0.22

MutPred

0.36

.;Loss of helix (P = 0.079);.;.;.;.;.;.;

MVP

0.36

MPC

0.25

ClinPred

0.065

GERP RS

3.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.19

gMVP

0.22

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.00020

dbscSNV1_RF

Benign

0.012

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