22-42799049-G-C

Variant names:

• chr22-42799049-G-C
• NM_014570.5:c.1523C>G

Variant summary

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

The NM_014570.5(ARFGAP3):​c.1523C>G​(p.Thr508Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 33)
• Consequence: ARFGAP3 NM_014570.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.06

Genes affected

ARFGAP3 (HGNC:661): (ADP ribosylation factor GTPase activating protein 3) The protein encoded by this gene is a GTPase-activating protein (GAP) that associates with the Golgi apparatus and regulates the early secretory pathway of proteins. The encoded protein promotes hydrolysis of ADP-ribosylation factor 1 (ARF1)-bound GTP, which is required for the dissociation of coat proteins from Golgi-derived membranes and vesicles. Dissociation of the coat proteins is a prerequisite for the fusion of these vesicles with target compartments. The activity of this protein is sensitive to phospholipids. Multiple transcript variants encoding different isoforms have been found for this gene. This gene was originally known as ARFGAP1, but that is now the name of a related but different gene. [provided by RefSeq, Nov 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ARFGAP3	NM_014570.5	c.1523C>G	p.Thr508Ser	missense_variant	Exon 15 of 16	ENST00000263245.10	NP_055385.3
ARFGAP3	NM_001142293.2	c.1391C>G	p.Thr464Ser	missense_variant	Exon 14 of 15		NP_001135765.1
ARFGAP3	XM_005261525.5	c.1391C>G	p.Thr464Ser	missense_variant	Exon 14 of 15		XP_005261582.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ARFGAP3	ENST00000263245.10	c.1523C>G	p.Thr508Ser	missense_variant	Exon 15 of 16	1	NM_014570.5	ENSP00000263245.5
ARFGAP3	ENST00000437119.6	c.1391C>G	p.Thr464Ser	missense_variant	Exon 14 of 15	1		ENSP00000388791.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Mar 06, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1523C>G (p.T508S) alteration is located in exon 15 (coding exon 15) of the ARFGAP3 gene. This alteration results from a C to G substitution at nucleotide position 1523, causing the threonine (T) at amino acid position 508 to be replaced by a serine (S). 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	0.074
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.49
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.0058	T;.
Eigen	Benign	-0.25
Eigen_PC	Benign	-0.094
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Uncertain	0.86	D;T
M_CAP	Benign	0.0063	T
MetaRNN	Benign	0.13	T;T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	1.4	L;.
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	-0.55	N;N
REVEL	Benign	0.046
Sift	Benign	0.70	T;T
Sift4G	Benign	1.0	T;T
Polyphen		0.68	P;.
Vest4		0.25
MutPred		0.34		Gain of disorder (P = 0.045);.;
MVP		0.39
MPC		0.091
ClinPred		0.61	D
GERP RS		3.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.056
gMVP		0.28

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.27		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.27		Position offset: -10

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr22-43195055;