NM_014570.5:c.40A>C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

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

Scores

1
5
13

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.80
Variant links:
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]

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ACMG classification

Classification made for transcript

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
ARFGAP3NM_014570.5 linkc.40A>C p.Lys14Gln missense_variant Exon 1 of 16 ENST00000263245.10 NP_055385.3 Q9NP61-1A0A024R4U0
ARFGAP3NM_001142293.2 linkc.40A>C p.Lys14Gln missense_variant Exon 1 of 15 NP_001135765.1 Q9NP61-2
ARFGAP3XM_005261525.5 linkc.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
ARFGAP3ENST00000263245.10 linkc.40A>C p.Lys14Gln missense_variant Exon 1 of 16 1 NM_014570.5 ENSP00000263245.5 Q9NP61-1

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
show subpopulations
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
LINK: link

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; API