rs139659618

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The NM_020754.4(ARHGAP31):​c.2344C>A​(p.Pro782Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000304 in 1,614,186 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0015 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00018 ( 0 hom. )

Consequence

ARHGAP31
NM_020754.4 missense

Scores

1
18

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:5

Conservation

PhyloP100: 0.670
Variant links:
Genes affected
ARHGAP31 (HGNC:29216): (Rho GTPase activating protein 31) This gene encodes a GTPase-activating protein (GAP). A variety of cellular processes are regulated by Rho GTPases which cycle between an inactive form bound to GDP and an active form bound to GTP. This cycling between inactive and active forms is regulated by guanine nucleotide exchange factors and GAPs. The encoded protein is a GAP shown to regulate two GTPases involved in protein trafficking and cell growth. [provided by RefSeq, Jul 2008]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -9 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.0038205683).
BP6
Variant 3-119414273-C-A is Benign according to our data. Variant chr3-119414273-C-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 235226.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=1, Benign=1}.
BS2
High AC in GnomAd4 at 224 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
ARHGAP31NM_020754.4 linkuse as main transcriptc.2344C>A p.Pro782Thr missense_variant 12/12 ENST00000264245.9 NP_065805.2 Q2M1Z3A0A8S0MHV1
ARHGAP31XM_006713714.4 linkuse as main transcriptc.2284C>A p.Pro762Thr missense_variant 12/12 XP_006713777.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
ARHGAP31ENST00000264245.9 linkuse as main transcriptc.2344C>A p.Pro782Thr missense_variant 12/121 NM_020754.4 ENSP00000264245.4 Q2M1Z3

Frequencies

GnomAD3 genomes
AF:
0.00147
AC:
223
AN:
152180
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00444
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00170
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.000414
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.000118
Gnomad OTH
AF:
0.00144
GnomAD3 exomes
AF:
0.000425
AC:
106
AN:
249188
Hom.:
0
AF XY:
0.000385
AC XY:
52
AN XY:
135170
show subpopulations
Gnomad AFR exome
AF:
0.00439
Gnomad AMR exome
AF:
0.000753
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:
0.0000885
Gnomad OTH exome
AF:
0.000330
GnomAD4 exome
AF:
0.000182
AC:
266
AN:
1461888
Hom.:
0
Cov.:
30
AF XY:
0.000182
AC XY:
132
AN XY:
727244
show subpopulations
Gnomad4 AFR exome
AF:
0.00406
Gnomad4 AMR exome
AF:
0.000715
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000232
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000504
Gnomad4 OTH exome
AF:
0.000580
GnomAD4 genome
AF:
0.00147
AC:
224
AN:
152298
Hom.:
0
Cov.:
32
AF XY:
0.00165
AC XY:
123
AN XY:
74474
show subpopulations
Gnomad4 AFR
AF:
0.00445
Gnomad4 AMR
AF:
0.00170
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.000415
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.000118
Gnomad4 OTH
AF:
0.00142
Alfa
AF:
0.000325
Hom.:
0
Bravo
AF:
0.00156
TwinsUK
AF:
0.000270
AC:
1
ALSPAC
AF:
0.00
AC:
0
ESP6500AA
AF:
0.00335
AC:
13
ESP6500EA
AF:
0.00
AC:
0
ExAC
AF:
0.000414
AC:
50
Asia WGS
AF:
0.000866
AC:
3
AN:
3478
EpiCase
AF:
0.000164
EpiControl
AF:
0.00

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:1Benign:5
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not provided Uncertain:1Benign:2
Likely benign, criteria provided, single submitterclinical testingCenter for Pediatric Genomic Medicine, Children's Mercy Hospital and ClinicsApr 28, 2016- -
Likely benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 09, 2024- -
Uncertain significance, criteria provided, single submitterclinical testingGeneDxFeb 17, 2020In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -
not specified Benign:1
Benign, criteria provided, single submitterclinical testingEurofins Ntd Llc (ga)Oct 11, 2016- -
ARHGAP31-related disorder Benign:1
Likely benign, no assertion criteria providedclinical testingPreventionGenetics, part of Exact SciencesMar 04, 2019This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -
Inborn genetic diseases Benign:1
Likely benign, criteria provided, single submitterclinical testingAmbry GeneticsJun 03, 2024This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.12
BayesDel_addAF
Benign
-0.61
T
BayesDel_noAF
Benign
-0.65
CADD
Benign
16
DANN
Benign
0.88
DEOGEN2
Benign
0.0061
T
Eigen
Benign
-1.0
Eigen_PC
Benign
-1.0
FATHMM_MKL
Benign
0.36
N
LIST_S2
Benign
0.63
T
M_CAP
Benign
0.0030
T
MetaRNN
Benign
0.0038
T
MetaSVM
Benign
-0.93
T
MutationAssessor
Uncertain
2.4
M
PrimateAI
Benign
0.36
T
PROVEAN
Benign
-0.43
N
REVEL
Benign
0.028
Sift
Benign
0.15
T
Sift4G
Benign
0.67
T
Polyphen
0.0
B
Vest4
0.16
MVP
0.068
MPC
0.044
ClinPred
0.0087
T
GERP RS
2.6
Varity_R
0.029
gMVP
0.42

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

LitVar

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

Other links and lift over

dbSNP: rs139659618; hg19: chr3-119133120; API