chr20-63278927-G-C

Variant names:

• chr20-63278927-G-C
• rs1601343366
• NM_018209.4:c.559G>C

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_018209.4(ARFGAP1):​c.559G>C​(p.Gly187Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,826 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 14/22 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: ARFGAP1 NM_018209.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.23
• Publications: 0 publications found

Genes affected

ARFGAP1 (HGNC:15852): (ADP ribosylation factor GTPase activating protein 1) The protein encoded by this gene is a GTPase-activating protein, which associates with the Golgi apparatus and which interacts with ADP-ribosylation factor 1. The encoded protein promotes hydrolysis of ADP-ribosylation factor 1-bound GTP and is required for the dissociation of coat proteins from Golgi-derived membranes and vesicles. Dissociation of the coat proteins is required for the fusion of these vesicles with target compartments. The activity of this protein is stimulated by phosphoinosides and inhibited by phosphatidylcholine. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jul 2013]

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.869

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ARFGAP1	NM_018209.4	c.559G>C	p.Gly187Arg	missense_variant	Exon 7 of 13	ENST00000370283.9	NP_060679.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ARFGAP1	ENST00000370283.9	c.559G>C	p.Gly187Arg	missense_variant	Exon 7 of 13	1	NM_018209.4	ENSP00000359306.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461826 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727198

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53376

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1111994

Other (OTH) AF: 0.00 AC: 0 AN: 60392

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Apr 03, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.559G>C (p.G187R) alteration is located in exon 7 (coding exon 6) of the ARFGAP1 gene. This alteration results from a G to C substitution at nucleotide position 559, causing the glycine (G) at amino acid position 187 to be replaced by an arginine (R). 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	Pathogenic	0.92
BayesDel_addAF	Pathogenic	0.47	D
BayesDel_noAF	Pathogenic	0.44
CADD	Pathogenic	29
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.57	.;.;D;.;D;.;.;.;.
Eigen	Pathogenic	0.92
Eigen_PC	Pathogenic	0.86
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.97	D;D;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.41	D
MetaRNN	Pathogenic	0.87	D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	0.89	D
MutationAssessor	Pathogenic	3.0	.;.;M;.;.;M;.;M;.
PhyloP100		9.2
PrimateAI	Pathogenic	0.80	T
PROVEAN	Pathogenic	-6.6	D;D;D;D;D;D;D;D;D
REVEL	Pathogenic	0.73
Sift	Uncertain	0.0010	D;D;D;D;D;D;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;D;D;D;D;D;D
Polyphen		1.0	.;.;D;.;.;.;.;D;.
Vest4		0.96
MutPred		0.37		.;.;Gain of catalytic residue at G187 (P = 0.0344);.;.;Gain of catalytic residue at G187 (P = 0.0344);.;Gain of catalytic residue at G187 (P = 0.0344);Gain of catalytic residue at G187 (P = 0.0344);
MVP		0.99
MPC		0.64
ClinPred		1.0	D
GERP RS		5.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.81
gMVP		0.90
Mutation Taster		=0/100	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1601343366; hg19: chr20-61910279;