rs765634709

Variant names:

• chr22-37625898-G-A
• rs765634709
• NM_013365.5:c.1042G>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_013365.5(GGA1):​c.1042G>A​(p.Glu348Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000622 in 1,607,988 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000048 (0 hom.)
• Consequence: GGA1 NM_013365.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.09
• Publications: 0 publications found

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]

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.07497445).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_013365.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GGA1	NM_013365.5	MANE Select	c.1042G>A	p.Glu348Lys	missense	Exon 11 of 17	NP_037497.1	Q9UJY5-1
	GGA1	NM_001363771.2		c.1093G>A	p.Glu365Lys	missense	Exon 11 of 17	NP_001350700.1	Q9UJY5-6
	GGA1	NM_001172687.2		c.1042G>A	p.Glu348Lys	missense	Exon 11 of 17	NP_001166158.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GGA1	ENST00000343632.9	TSL:1 MANE Select	c.1042G>A	p.Glu348Lys	missense	Exon 11 of 17	ENSP00000341344.4	Q9UJY5-1
	GGA1	ENST00000381756.9	TSL:1	c.1093G>A	p.Glu365Lys	missense	Exon 11 of 17	ENSP00000371175.5	Q9UJY5-6
	GGA1	ENST00000325180.12	TSL:1	c.832+2265G>A		intron	N/A	ENSP00000321288.8	Q9UJY5-4

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152188 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

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

GnomAD2 exomes AF: 0.0000202 AC: 5 AN: 247750 AF XY: 0.0000224

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000116

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000165

GnomAD4 exome AF: 0.00000481 AC: 7 AN: 1455800 Hom.: 0 Cov.: 31 AF XY: 0.00000414 AC XY: 3 AN XY: 724436

African (AFR) AF: 0.00 AC: 0 AN: 33448

American (AMR) AF: 0.000112 AC: 5 AN: 44618

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26036

East Asian (EAS) AF: 0.00 AC: 0 AN: 39628

South Asian (SAS) AF: 0.00 AC: 0 AN: 85946

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50630

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5752

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1109608

Other (OTH) AF: 0.0000333 AC: 2 AN: 60134

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152188 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74346

African (AFR) AF: 0.0000241 AC: 1 AN: 41452

American (AMR) AF: 0.000131 AC: 2 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68024

Other (OTH) AF: 0.00 AC: 0 AN: 2088

Alfa AF: 0.0000434 Hom.: 0

Bravo AF: 0.0000982

ExAC AF: 0.0000165 AC: 2

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.077
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.57
CADD	Benign	17
DANN	Benign	0.68
DEOGEN2	Benign	0.073	T
Eigen	Benign	-0.61
Eigen_PC	Benign	-0.50
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.67	T
M_CAP	Benign	0.016	T
MetaRNN	Benign	0.075	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.90	L
PhyloP100		2.1
PrimateAI	Benign	0.46	T
PROVEAN	Benign	-0.64	N
REVEL	Benign	0.069
Sift	Benign	0.72	T
Sift4G	Benign	0.84	T
Polyphen		0.0	B
Vest4		0.22
MutPred		0.26		Gain of ubiquitination at E365 (P = 0.0029)
MVP		0.30
MPC		0.29
ClinPred		0.020	T
GERP RS		3.6
Varity_R		0.076
gMVP		0.30
Mutation Taster		=92/8	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs765634709; hg19: chr22-38021905;