17-75239537-G-C

Variant names:

• chr17-75239537-G-C
• rs1004521080
• NM_138619.4:c.1618C>G

Variant summary

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

The NM_138619.4(GGA3):​c.1618C>G​(p.Leu540Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000708 in 1,411,512 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 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: 7.1e-7 (0 hom.)
• Consequence: GGA3 NM_138619.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.36
• Publications: 0 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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.10582322).

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.1618C>G	p.Leu540Val	missense	Exon 14 of 17	NP_619525.1	Q9NZ52-1
	GGA3	NM_014001.5		c.1519C>G	p.Leu507Val	missense	Exon 13 of 16	NP_054720.1	Q9NZ52-2
	GGA3	NM_001172703.3		c.1402C>G	p.Leu468Val	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.1618C>G	p.Leu540Val	missense	Exon 14 of 17	ENSP00000438085.3	Q9NZ52-1
	GGA3	ENST00000538886.5	TSL:1	c.1519C>G	p.Leu507Val	missense	Exon 13 of 16	ENSP00000446421.2	Q9NZ52-2
	GGA3	ENST00000621870.4	TSL:1	n.*1577C>G		non_coding_transcript_exon	Exon 15 of 18	ENSP00000479464.1	G3V1K5

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 7.08e-7 AC: 1 AN: 1411512 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 698744

African (AFR) AF: 0.00 AC: 0 AN: 31848

American (AMR) AF: 0.00 AC: 0 AN: 34790

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25084

East Asian (EAS) AF: 0.00 AC: 0 AN: 36984

South Asian (SAS) AF: 0.00 AC: 0 AN: 81230

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50080

Middle Eastern (MID) AF: 0.000177 AC: 1 AN: 5654

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1087408

Other (OTH) AF: 0.00 AC: 0 AN: 58434

GnomAD4 genome Cov.: 31

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	0.057
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.49
CADD	Benign	15
DANN	Benign	0.73
DEOGEN2	Benign	0.031	T
Eigen	Benign	-0.48
Eigen_PC	Benign	-0.49
FATHMM_MKL	Benign	0.29	N
LIST_S2	Uncertain	0.87	D
M_CAP	Benign	0.0074	T
MetaRNN	Benign	0.11	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.4	M
PhyloP100		1.4
PrimateAI	Benign	0.31	T
REVEL	Benign	0.035
Sift4G	Benign	0.46	T
Polyphen		0.13	B
Vest4		0.26
MutPred		0.20		Loss of glycosylation at P539 (P = 0.1429)
MVP		0.40
ClinPred		0.16	T
GERP RS		3.4
PromoterAI		0.015	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.11
gMVP		0.19
Mutation Taster		=95/5	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: rs1004521080; hg19: chr17-73235618;