chr20-63278994-C-G

Variant summary

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

The NM_018209.4(ARFGAP1):​c.626C>G​(p.Ser209Trp) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,500 control chromosomes in the GnomAD database, with no homozygous occurrence. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S209L) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)
Exomes 𝑓: 0.0000027 ( 0 hom. )

Consequence

ARFGAP1
NM_018209.4 missense, splice_region

Scores

6
11
2
Splicing: ADA: 0.9585
1
1

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.30

Publications

0 publications found
Variant links:
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]

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 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
ARFGAP1NM_018209.4 linkc.626C>G p.Ser209Trp missense_variant, splice_region_variant Exon 7 of 13 ENST00000370283.9 NP_060679.1 Q8N6T3-1Q53F62

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
ARFGAP1ENST00000370283.9 linkc.626C>G p.Ser209Trp missense_variant, splice_region_variant Exon 7 of 13 1 NM_018209.4 ENSP00000359306.4 Q8N6T3-1

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
AF:
0.00000274
AC:
4
AN:
1461500
Hom.:
0
Cov.:
31
AF XY:
0.00000413
AC XY:
3
AN XY:
727040
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
33474
American (AMR)
AF:
0.00
AC:
0
AN:
44720
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:
86250
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
53112
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5768
European-Non Finnish (NFE)
AF:
0.00000360
AC:
4
AN:
1111954
Other (OTH)
AF:
0.00
AC:
0
AN:
60386
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.463
Heterozygous variant carriers
0
1
1
2
2
3
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Variant carriers
0
2
4
6
8
10
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
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
Jan 29, 2025
Ambry Genetics
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

The c.626C>G (p.S209W) alteration is located in exon 7 (coding exon 6) of the ARFGAP1 gene. This alteration results from a C to G substitution at nucleotide position 626, causing the serine (S) at amino acid position 209 to be replaced by a tryptophan (W). 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
Uncertain
0.42
BayesDel_addAF
Uncertain
0.16
D
BayesDel_noAF
Uncertain
-0.010
CADD
Pathogenic
33
DANN
Uncertain
0.99
DEOGEN2
Benign
0.32
.;.;T;.;T;.;.;.;.
Eigen
Pathogenic
0.80
Eigen_PC
Pathogenic
0.75
FATHMM_MKL
Pathogenic
0.98
D
LIST_S2
Pathogenic
0.98
D;D;D;D;D;D;D;D;D
M_CAP
Uncertain
0.14
D
MetaRNN
Uncertain
0.54
D;D;D;D;D;D;D;D;D
MetaSVM
Uncertain
-0.22
T
MutationAssessor
Uncertain
2.9
.;.;M;.;.;M;.;M;.
PhyloP100
7.3
PrimateAI
Uncertain
0.63
T
PROVEAN
Pathogenic
-4.8
D;D;D;D;D;D;D;D;D
REVEL
Uncertain
0.53
Sift
Pathogenic
0.0
D;D;D;D;D;D;D;D;D
Sift4G
Uncertain
0.0030
D;D;D;D;D;D;D;D;D
Polyphen
1.0, 1.0
.;.;D;.;.;.;.;D;.
Vest4
0.74
MutPred
0.44
.;.;Loss of disorder (P = 4e-04);.;.;Loss of disorder (P = 4e-04);.;Loss of disorder (P = 4e-04);Loss of disorder (P = 4e-04);
MVP
0.82
MPC
0.68
ClinPred
1.0
D
GERP RS
5.2
Varity_R
0.80
gMVP
0.77
Mutation Taster
=42/58
disease causing

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
0.96
dbscSNV1_RF
Benign
0.66
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

Other links and lift over

dbSNP: rs375179520; hg19: chr20-61910346; API