17-75239458-C-T

Variant names:

• chr17-75239458-C-T
• rs1474076675
• NM_138619.4:c.1697G>A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_138619.4(GGA3):​c.1697G>A​(p.Ser566Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000021 in 1,429,138 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: GGA3 NM_138619.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.77

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.08093235).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GGA3	NM_138619.4	c.1697G>A	p.Ser566Asn	missense_variant	Exon 14 of 17	ENST00000537686.6	NP_619525.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GGA3	ENST00000537686.6	c.1697G>A	p.Ser566Asn	missense_variant	Exon 14 of 17	1	NM_138619.4	ENSP00000438085.3

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD3 exomes AF: 0.00000467 AC: 1 AN: 214162 Hom.: 0 AF XY: 0.00000852 AC XY: 1 AN XY: 117312

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: 0.0000399

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000210 AC: 3 AN: 1429138 Hom.: 0 Cov.: 32 AF XY: 0.00000422 AC XY: 3 AN XY: 710850

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: 0.0000370

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Sep 30, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1697G>A (p.S566N) alteration is located in exon 14 (coding exon 14) of the GGA3 gene. This alteration results from a G to A substitution at nucleotide position 1697, causing the serine (S) at amino acid position 566 to be replaced by an asparagine (N). 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	0.092
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.57
CADD	Benign	16
DANN	Benign	0.66
DEOGEN2	Benign	0.036	.;T;.;.;.
Eigen	Benign	-0.87
Eigen_PC	Benign	-0.87
FATHMM_MKL	Uncertain	0.78	D
LIST_S2	Benign	0.79	T;.;T;T;T
M_CAP	Benign	0.0090	T
MetaRNN	Benign	0.081	T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.77	.;N;.;.;.
PrimateAI	Benign	0.39	T
REVEL	Benign	0.026
Sift4G	Benign	0.17	T;T;T;T;T
Polyphen		0.12	B;B;.;.;.
Vest4		0.18
MutPred		0.15		.;Loss of phosphorylation at S566 (P = 0.0327);.;.;.;
MVP		0.21
ClinPred		0.036	T
GERP RS		1.4
Varity_R		0.060
gMVP		0.15

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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

Other links and lift over

dbSNP: rs1474076675; hg19: chr17-73235539;