chr20-63277289-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_018209.4(ARFGAP1):​c.427C>T​(p.Pro143Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000145 in 1,612,548 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00016 ( 0 hom. )

Consequence

ARFGAP1
NM_018209.4 missense

Scores

19

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.0750
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 Likely_benign. Variant got -2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.04869485).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
ARFGAP1NM_018209.4 linkc.427C>T p.Pro143Ser missense_variant Exon 5 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.427C>T p.Pro143Ser missense_variant Exon 5 of 13 1 NM_018209.4 ENSP00000359306.4 Q8N6T3-1

Frequencies

GnomAD3 genomes
AF:
0.0000263
AC:
4
AN:
152136
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000441
Gnomad OTH
AF:
0.000479
GnomAD3 exomes
AF:
0.0000201
AC:
5
AN:
249086
Hom.:
0
AF XY:
0.0000148
AC XY:
2
AN XY:
135176
show subpopulations
Gnomad AFR exome
AF:
0.00
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:
0.0000445
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.000157
AC:
230
AN:
1460412
Hom.:
0
Cov.:
31
AF XY:
0.000146
AC XY:
106
AN XY:
726544
show subpopulations
Gnomad4 AFR exome
AF:
0.0000299
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.000202
Gnomad4 OTH exome
AF:
0.0000663
GnomAD4 genome
AF:
0.0000263
AC:
4
AN:
152136
Hom.:
0
Cov.:
32
AF XY:
0.0000135
AC XY:
1
AN XY:
74320
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000441
Gnomad4 OTH
AF:
0.000479
Alfa
AF:
0.000134
Hom.:
0
Bravo
AF:
0.0000529
ExAC
AF:
0.0000247
AC:
3
EpiCase
AF:
0.000109
EpiControl
AF:
0.000119

ClinVar

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

Submissions by phenotype

not specified Uncertain:1
Mar 24, 2023
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.427C>T (p.P143S) alteration is located in exon 5 (coding exon 4) of the ARFGAP1 gene. This alteration results from a C to T substitution at nucleotide position 427, causing the proline (P) at amino acid position 143 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
0.067
BayesDel_addAF
Benign
-0.40
T
BayesDel_noAF
Benign
-0.68
CADD
Benign
0.83
DANN
Benign
0.72
DEOGEN2
Benign
0.0072
.;T;.;T;.;.;.;.
Eigen
Benign
-1.3
Eigen_PC
Benign
-1.3
FATHMM_MKL
Benign
0.28
N
LIST_S2
Benign
0.79
T;T;T;T;T;T;T;T
M_CAP
Benign
0.0094
T
MetaRNN
Benign
0.049
T;T;T;T;T;T;T;T
MetaSVM
Benign
-1.0
T
MutationAssessor
Benign
0.14
.;N;.;.;N;.;N;.
PrimateAI
Benign
0.23
T
PROVEAN
Benign
0.44
N;N;N;N;N;N;N;N
REVEL
Benign
0.014
Sift
Benign
0.83
T;T;T;T;T;T;T;T
Sift4G
Benign
0.76
T;T;T;T;T;T;T;T
Polyphen
0.0010
.;B;.;.;.;.;B;.
Vest4
0.10
MVP
0.20
MPC
0.13
ClinPred
0.043
T
GERP RS
-2.0
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.1
Varity_R
0.024
gMVP
0.17

Splicing

Name
Calibrated prediction
Score
Prediction
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: rs756677561; hg19: chr20-61908641; API