rs147131853

Variant summary

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

The NM_004840.3(ARHGEF6):ā€‹c.169T>Cā€‹(p.Cys57Arg) variant causes a missense change. The variant allele was found at a frequency of 0.000351 in 1,203,906 control chromosomes in the GnomAD database, including 1 homozygotes. There are 102 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: š‘“ 0.0018 ( 0 hom., 47 hem., cov: 23)
Exomes š‘“: 0.00020 ( 1 hom. 55 hem. )

Consequence

ARHGEF6
NM_004840.3 missense

Scores

3
5
9

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:3

Conservation

PhyloP100: 5.50
Variant links:
Genes affected
ARHGEF6 (HGNC:685): (Rac/Cdc42 guanine nucleotide exchange factor 6) Rho GTPases play a fundamental role in numerous cellular processes that are initiated by extracellular stimuli that work through G protein coupled receptors. The encoded protein belongs to a family of cytoplasmic proteins that activate the Ras-like family of Rho proteins by exchanging bound GDP for GTP. It may form a complex with G proteins and stimulate Rho-dependent signals. This protein is activated by PI3-kinase. Mutations in this gene can cause X-chromosomal non-specific cognitive disability. [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=0.014819652).
BP6
Variant X-136779494-A-G is Benign according to our data. Variant chrX-136779494-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 210251.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Benign=1, Uncertain_significance=1}. Variant chrX-136779494-A-G is described in Lovd as [Likely_benign].
BS2
High Hemizygotes in GnomAd4 at 47 XL gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
ARHGEF6NM_004840.3 linkuse as main transcriptc.169T>C p.Cys57Arg missense_variant 2/22 ENST00000250617.7 NP_004831.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
ARHGEF6ENST00000250617.7 linkuse as main transcriptc.169T>C p.Cys57Arg missense_variant 2/221 NM_004840.3 ENSP00000250617 P1Q15052-1

Frequencies

GnomAD3 genomes
AF:
0.00181
AC:
202
AN:
111815
Hom.:
0
Cov.:
23
AF XY:
0.00135
AC XY:
46
AN XY:
33985
show subpopulations
Gnomad AFR
AF:
0.00619
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000858
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:
0.0000188
Gnomad OTH
AF:
0.00133
GnomAD3 exomes
AF:
0.000611
AC:
112
AN:
183413
Hom.:
0
AF XY:
0.000295
AC XY:
20
AN XY:
67859
show subpopulations
Gnomad AFR exome
AF:
0.00745
Gnomad AMR exome
AF:
0.000365
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:
0.0000366
Gnomad OTH exome
AF:
0.000221
GnomAD4 exome
AF:
0.000201
AC:
220
AN:
1092036
Hom.:
1
Cov.:
29
AF XY:
0.000154
AC XY:
55
AN XY:
357694
show subpopulations
Gnomad4 AFR exome
AF:
0.00662
Gnomad4 AMR exome
AF:
0.000540
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:
0.0000108
Gnomad4 OTH exome
AF:
0.000305
GnomAD4 genome
AF:
0.00181
AC:
203
AN:
111870
Hom.:
0
Cov.:
23
AF XY:
0.00138
AC XY:
47
AN XY:
34050
show subpopulations
Gnomad4 AFR
AF:
0.00621
Gnomad4 AMR
AF:
0.000857
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000188
Gnomad4 OTH
AF:
0.00131
Alfa
AF:
0.000208
Hom.:
6
Bravo
AF:
0.00201
ESP6500AA
AF:
0.00756
AC:
29
ESP6500EA
AF:
0.00
AC:
0
ExAC
AF:
0.000585
AC:
71
EpiCase
AF:
0.00
EpiControl
AF:
0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:1Benign:3
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingGenetic Services Laboratory, University of ChicagoMay 12, 2015- -
not provided Benign:1
Benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpDec 31, 2019- -
Intellectual disability, X-linked 46 Benign:1
Likely benign, criteria provided, single submitterclinical testingMendelicsMay 28, 2019- -
History of neurodevelopmental disorder Benign:1
Likely benign, criteria provided, single submitterclinical testingAmbry GeneticsMay 15, 2013This alteration is classified as likely benign based on a combination of the following: 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
0.18
BayesDel_addAF
Benign
-0.019
T
BayesDel_noAF
Pathogenic
0.20
CADD
Uncertain
23
DANN
Uncertain
0.99
DEOGEN2
Uncertain
0.68
D
FATHMM_MKL
Uncertain
0.93
D
LIST_S2
Benign
0.71
T
M_CAP
Pathogenic
0.51
D
MetaRNN
Benign
0.015
T
MetaSVM
Uncertain
0.66
D
MutationAssessor
Benign
1.2
L
MutationTaster
Benign
1.0
D
PrimateAI
Uncertain
0.53
T
PROVEAN
Benign
-2.2
N
REVEL
Pathogenic
0.84
Sift
Benign
0.050
D
Sift4G
Benign
0.24
T
Polyphen
0.99
D
Vest4
0.52
MVP
0.97
MPC
0.93
ClinPred
0.040
T
GERP RS
4.6
Varity_R
0.93
gMVP
0.74

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: rs147131853; hg19: chrX-135861653; API