Variant chr22-37620860-C-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_013365.5(GGA1):c.475C>T(p.Leu159Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000342 in 1,460,718 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/23 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000034 ( 0 hom. )

Consequence

GGA1
NM_013365.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.724

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 Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GGA1	NM_013365.5 linkuse as main transcript	c.475C>T	p.Leu159Phe	missense_variant	6/17	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.475C>T	p.Leu159Phe	missense_variant	6/17	1	NM_013365.5	ENSP00000341344.4		Q9UJY5-1
GGA1	ENST00000381756.9 linkuse as main transcript	c.526C>T	p.Leu176Phe	missense_variant	6/17	1		ENSP00000371175.5		Q9UJY5-6

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000342

AC:

AN:

1460718

Hom.:

Cov.:

AF XY:

0.00000413

AC XY:

AN XY:

726748

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:

0.00000450

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

May 31, 2023

The c.475C>T (p.L159F) alteration is located in exon 6 (coding exon 6) of the GGA1 gene. This alteration results from a C to T substitution at nucleotide position 475, causing the leucine (L) at amino acid position 159 to be replaced by a phenylalanine (F). 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

0.081

BayesDel_addAF

Benign

-0.21

BayesDel_noAF

Benign

-0.54

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.23

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

Eigen

Benign

-0.61

Eigen_PC

Benign

-0.63

FATHMM_MKL

Benign

0.27

LIST_S2

Uncertain

0.93

D;D;.;D;D;D;.;T

M_CAP

Benign

0.015

MetaRNN

Benign

0.071

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

MetaSVM

Benign

-0.95

MutationAssessor

Benign

1.4

L;.;.;L;.;.;.;.

PrimateAI

Benign

0.28

PROVEAN

Benign

-1.5

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

REVEL

Benign

0.080

Sift

Benign

0.087

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

Sift4G

Benign

0.069

T;T;T;T;T;D;T;T

Polyphen

0.041

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

Vest4

0.24

MutPred

0.34

.;Gain of glycosylation at T173 (P = 0.1512);.;.;.;.;.;.;

MVP

0.28

MPC

0.37

ClinPred

0.32

GERP RS

-1.8

Varity_R

0.063

gMVP

0.15

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.24

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.24

Position offset: 21

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