17-75239451-C-G

Variant names:

• chr17-75239451-C-G
• rs375885510
• NM_138619.4:c.1704G>C

Variant summary

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

The NM_138619.4(GGA3):​c.1704G>C​(p.Gln568His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000506 in 1,580,940 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 0.0000066 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0000049 (0 hom.)
• Consequence: GGA3 NM_138619.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.563
• Publications: 1 publications found

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

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_138619.4. 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
	GGA3	NM_138619.4	MANE Select	c.1704G>C	p.Gln568His	missense	Exon 14 of 17	NP_619525.1	Q9NZ52-1
	GGA3	NM_014001.5		c.1605G>C	p.Gln535His	missense	Exon 13 of 16	NP_054720.1	Q9NZ52-2
	GGA3	NM_001172703.3		c.1488G>C	p.Gln496His	missense	Exon 14 of 17	NP_001166174.1	Q9NZ52-4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GGA3	ENST00000537686.6	TSL:1 MANE Select	c.1704G>C	p.Gln568His	missense	Exon 14 of 17	ENSP00000438085.3	Q9NZ52-1
	GGA3	ENST00000538886.5	TSL:1	c.1605G>C	p.Gln535His	missense	Exon 13 of 16	ENSP00000446421.2	Q9NZ52-2
	GGA3	ENST00000621870.4	TSL:1	n.*1663G>C		non_coding_transcript_exon	Exon 15 of 18	ENSP00000479464.1	G3V1K5

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152098 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000931 AC: 2 AN: 214864 AF XY: 0.0000170

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000195

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000490 AC: 7 AN: 1428842 Hom.: 0 Cov.: 32 AF XY: 0.00000563 AC XY: 4 AN XY: 710732

African (AFR) AF: 0.00 AC: 0 AN: 31030

American (AMR) AF: 0.00 AC: 0 AN: 32284

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24214

East Asian (EAS) AF: 0.00 AC: 0 AN: 39558

South Asian (SAS) AF: 0.00 AC: 0 AN: 81194

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52834

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5616

European-Non Finnish (NFE) AF: 0.00000635 AC: 7 AN: 1103160

Other (OTH) AF: 0.00 AC: 0 AN: 58952

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152098 Hom.: 0 Cov.: 31 AF XY: 0.0000135 AC XY: 1 AN XY: 74298

African (AFR) AF: 0.00 AC: 0 AN: 41416

American (AMR) AF: 0.00 AC: 0 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10606

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

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68008

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.0000247 AC: 3

ClinVar

ClinVar submissions as Germline

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	0.087
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.40
CADD	Benign	15
DANN	Benign	0.70
DEOGEN2	Benign	0.033	T
Eigen	Benign	-0.082
Eigen_PC	Benign	-0.16
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Benign	0.75	T
M_CAP	Benign	0.0051	T
MetaRNN	Benign	0.20	T
MetaSVM	Benign	-0.95	T
MutationAssessor	Uncertain	2.1	M
PhyloP100		0.56
PrimateAI	Benign	0.37	T
PROVEAN	Pathogenic	-4.5	D
REVEL	Benign	0.042
Sift	Uncertain	0.0010	D
Sift4G	Benign	0.11	T
Polyphen		0.95	P
Vest4		0.32
MutPred		0.10		Loss of glycosylation at P573 (P = 0.1843)
MVP		0.39
ClinPred		0.80	D
GERP RS		2.6
PromoterAI		-0.0026	Neutral
Varity_R		0.056
gMVP		0.32
Mutation Taster		=91/9	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.22		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.22		Position offset: -7

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

Other links and lift over

dbSNP: rs375885510; hg19: chr17-73235532;