chr17-8312119-G-A

Variant summary

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

The NM_173728.4(ARHGEF15):​c.80G>A​(p.Arg27His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000616 in 1,379,258 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: 𝑓 0.00046 ( 0 hom., cov: 20)
Exomes 𝑓: 0.000031 ( 0 hom. )

Consequence

ARHGEF15
NM_173728.4 missense

Scores

8
11

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 3.38
Variant links:
Genes affected
ARHGEF15 (HGNC:15590): (Rho guanine nucleotide exchange factor 15) Rho GTPases play a fundamental role in numerous cellular processes that are initiated by extracellular stimuli that work through G protein-coupled receptors. This gene encodes a protein that functions as a specific guanine nucleotide exchange factor for RhoA. It also interacts with ephrin A4 in vascular smooth muscle cells. Two alternatively spliced transcripts variants that encode the same protein have been found for this gene. [provided by RefSeq, Aug 2010]

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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=0.030038357).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
ARHGEF15NM_173728.4 linkuse as main transcriptc.80G>A p.Arg27His missense_variant 2/16 ENST00000361926.8 NP_776089.2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
ARHGEF15ENST00000361926.8 linkuse as main transcriptc.80G>A p.Arg27His missense_variant 2/161 NM_173728.4 ENSP00000355026 P1

Frequencies

GnomAD3 genomes
AF:
0.000457
AC:
46
AN:
100590
Hom.:
0
Cov.:
20
show subpopulations
Gnomad AFR
AF:
0.0000816
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00546
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:
0.00
Gnomad OTH
AF:
0.00154
GnomAD3 exomes
AF:
0.0000494
AC:
9
AN:
182036
Hom.:
0
AF XY:
0.0000299
AC XY:
3
AN XY:
100284
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.000195
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:
0.0000114
Gnomad OTH exome
AF:
0.00104
GnomAD4 exome
AF:
0.0000305
AC:
39
AN:
1278664
Hom.:
0
Cov.:
39
AF XY:
0.0000223
AC XY:
14
AN XY:
628156
show subpopulations
Gnomad4 AFR exome
AF:
0.0000360
Gnomad4 AMR exome
AF:
0.000831
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:
0.00000297
Gnomad4 OTH exome
AF:
0.000137
GnomAD4 genome
AF:
0.000457
AC:
46
AN:
100594
Hom.:
0
Cov.:
20
AF XY:
0.000489
AC XY:
23
AN XY:
47044
show subpopulations
Gnomad4 AFR
AF:
0.0000815
Gnomad4 AMR
AF:
0.00545
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00153
Alfa
AF:
0.0000454
Hom.:
0
Bravo
AF:
0.000797
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.000116
AC:
1
ExAC
AF:
0.0000165
AC:
2

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Early infantile epileptic encephalopathy with suppression bursts Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpDec 09, 2023This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 27 of the ARHGEF15 protein (p.Arg27His). This variant is present in population databases (rs199663714, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with ARHGEF15-related conditions. ClinVar contains an entry for this variant (Variation ID: 461440). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
not provided Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingNew York Genome CenterJul 27, 2020- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.13
BayesDel_addAF
Benign
-0.17
T
BayesDel_noAF
Benign
-0.20
CADD
Pathogenic
27
DANN
Uncertain
0.98
DEOGEN2
Benign
0.056
.;T;.;T
Eigen
Uncertain
0.50
Eigen_PC
Uncertain
0.50
FATHMM_MKL
Uncertain
0.89
D
LIST_S2
Benign
0.75
T;.;T;T
M_CAP
Uncertain
0.18
D
MetaRNN
Benign
0.030
T;T;T;T
MetaSVM
Benign
-0.38
T
MutationAssessor
Uncertain
2.0
.;M;.;M
MutationTaster
Benign
0.96
N;N
PrimateAI
Uncertain
0.59
T
PROVEAN
Benign
-0.090
.;N;.;N
REVEL
Benign
0.24
Sift
Uncertain
0.0010
.;D;.;D
Sift4G
Benign
0.075
T;D;T;D
Polyphen
1.0
.;D;.;D
Vest4
0.39, 0.40
MVP
0.87
MPC
0.50
ClinPred
0.27
T
GERP RS
5.0
Varity_R
0.10
gMVP
0.29

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: rs199663714; hg19: chr17-8215437; API