20-63278994-C-T

Variant summary

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

The NM_018209.4(ARFGAP1):​c.626C>T​(p.Ser209Leu) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000479 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. S209W) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)
Exomes 𝑓: 0.0000048 ( 0 hom. )

Consequence

ARFGAP1
NM_018209.4 missense, splice_region

Scores

2
10
7
Splicing: ADA: 0.9581
1
1

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.30
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 made for transcript

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
ARFGAP1NM_018209.4 linkc.626C>T p.Ser209Leu 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>T p.Ser209Leu missense_variant, splice_region_variant Exon 7 of 13 1 NM_018209.4 ENSP00000359306.4 Q8N6T3-1

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD3 exomes
AF:
0.00000399
AC:
1
AN:
250318
Hom.:
0
AF XY:
0.00
AC XY:
0
AN XY:
135702
show subpopulations
Gnomad AFR exome
AF:
0.0000619
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000479
AC:
7
AN:
1461500
Hom.:
0
Cov.:
31
AF XY:
0.00000275
AC XY:
2
AN XY:
727040
show subpopulations
Gnomad4 AFR exome
AF:
0.0000597
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000756
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000180
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
33
Bravo
AF:
0.00000378
ESP6500AA
AF:
0.000227
AC:
1
ESP6500EA
AF:
0.00
AC:
0
ExAC
AF:
0.00000824
AC:
1

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Oct 01, 2024
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.626C>T (p.S209L) alteration is located in exon 7 (coding exon 6) of the ARFGAP1 gene. This alteration results from a C to T substitution at nucleotide position 626, causing the serine (S) at amino acid position 209 to be replaced by a leucine (L). 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
0.12
BayesDel_addAF
Benign
-0.00084
T
BayesDel_noAF
Uncertain
-0.060
CADD
Pathogenic
30
DANN
Pathogenic
1.0
DEOGEN2
Benign
0.21
.;.;T;.;T;.;.;.;.
Eigen
Uncertain
0.64
Eigen_PC
Uncertain
0.64
FATHMM_MKL
Pathogenic
0.98
D
LIST_S2
Uncertain
0.94
D;D;D;D;D;D;D;D;D
M_CAP
Benign
0.059
D
MetaRNN
Benign
0.41
T;T;T;T;T;T;T;T;T
MetaSVM
Benign
-0.45
T
MutationAssessor
Uncertain
2.9
.;.;M;.;.;M;.;M;.
PrimateAI
Uncertain
0.60
T
PROVEAN
Uncertain
-3.7
D;D;D;D;D;D;N;D;D
REVEL
Uncertain
0.31
Sift
Uncertain
0.0010
D;D;D;D;D;D;D;D;T
Sift4G
Uncertain
0.016
D;D;D;T;T;T;D;D;T
Polyphen
0.95, 0.99
.;.;P;.;.;.;.;D;.
Vest4
0.76
MVP
0.72
MPC
0.49
ClinPred
0.99
D
GERP RS
5.2
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
2.8
Varity_R
0.35
gMVP
0.67

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
0.96
dbscSNV1_RF
Benign
0.71
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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs375179520; hg19: chr20-61910346; API