NM_014570.5:c.40A>C

Variant names:

• chr22-42857143-T-G
• NM_014570.5:c.40A>C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_014570.5(ARFGAP3):​c.40A>C​(p.Lys14Gln) variant causes a missense change. The variant allele was found at a frequency of 0.0000022 in 1,362,940 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: not found (cov: 33)
  • Exomes 𝑓: 0.0000022 (0 hom.)
• Consequence: ARFGAP3 NM_014570.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.80

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]

PACSIN2 (HGNC:8571): (protein kinase C and casein kinase substrate in neurons 2) This gene is a member of the protein kinase C and casein kinase substrate in neurons family. The encoded protein is involved in linking the actin cytoskeleton with vesicle formation by regulating tubulin polymerization. Alternative splicing results in multiple transcript variants. [provided by RefSeq, May 2010]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.33574086).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ARFGAP3	NM_014570.5	c.40A>C	p.Lys14Gln	missense_variant	Exon 1 of 16	ENST00000263245.10	NP_055385.3
ARFGAP3	NM_001142293.2	c.40A>C	p.Lys14Gln	missense_variant	Exon 1 of 15		NP_001135765.1
ARFGAP3	XM_005261525.5	c.40A>C	p.Lys14Gln	missense_variant	Exon 1 of 15		XP_005261582.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ARFGAP3	ENST00000263245.10	c.40A>C	p.Lys14Gln	missense_variant	Exon 1 of 16	1	NM_014570.5	ENSP00000263245.5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000220 AC: 3 AN: 1362940 Hom.: 0 Cov.: 30 AF XY: 0.00000297 AC XY: 2 AN XY: 672514

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000131

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000188

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Feb 25, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.40A>C (p.K14Q) alteration is located in exon 1 (coding exon 1) of the ARFGAP3 gene. This alteration results from a A to C substitution at nucleotide position 40, causing the lysine (K) at amino acid position 14 to be replaced by a glutamine (Q). 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	0.25
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.41
CADD	Pathogenic	26
DANN	Uncertain	0.98
DEOGEN2	Benign	0.064	T;.;T
Eigen	Benign	0.12
Eigen_PC	Benign	0.21
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.95	D;D;D
M_CAP	Uncertain	0.23	D
MetaRNN	Benign	0.34	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.6	L;L;.
PrimateAI	Pathogenic	0.87	D
PROVEAN	Uncertain	-3.0	D;D;D
REVEL	Benign	0.10
Sift	Benign	0.055	T;T;D
Sift4G	Benign	0.065	T;T;T
Polyphen		0.17	B;.;.
Vest4		0.24
MutPred		0.47		Loss of methylation at K14 (P = 0.0367);Loss of methylation at K14 (P = 0.0367);Loss of methylation at K14 (P = 0.0367);
MVP		0.48
MPC		0.27
ClinPred		0.98	D
GERP RS		4.0
Varity_R		0.48
gMVP		0.50

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr22-43253149;