rs147131853
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Variant summary
Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2
The NM_004840.3(ARHGEF6):āc.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
NM_004840.3 missense
Scores
3
5
9
Clinical Significance
Conservation
PhyloP100: 5.50
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]
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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 |
---|---|---|---|---|---|---|---|---|
ARHGEF6 | NM_004840.3 | c.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 |
---|---|---|---|---|---|---|---|---|---|---|
ARHGEF6 | ENST00000250617.7 | c.169T>C | p.Cys57Arg | missense_variant | 2/22 | 1 | NM_004840.3 | ENSP00000250617 | P1 |
Frequencies
GnomAD3 genomes AF: 0.00181 AC: 202AN: 111815Hom.: 0 Cov.: 23 AF XY: 0.00135 AC XY: 46AN XY: 33985
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GnomAD3 exomes AF: 0.000611 AC: 112AN: 183413Hom.: 0 AF XY: 0.000295 AC XY: 20AN XY: 67859
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GnomAD4 exome AF: 0.000201 AC: 220AN: 1092036Hom.: 1 Cov.: 29 AF XY: 0.000154 AC XY: 55AN XY: 357694
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GnomAD4 genome AF: 0.00181 AC: 203AN: 111870Hom.: 0 Cov.: 23 AF XY: 0.00138 AC XY: 47AN XY: 34050
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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 submitter | clinical testing | Genetic Services Laboratory, University of Chicago | May 12, 2015 | - - |
not provided Benign:1
Benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Dec 31, 2019 | - - |
Intellectual disability, X-linked 46 Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Mendelics | May 28, 2019 | - - |
History of neurodevelopmental disorder Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | May 15, 2013 | This 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:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Pathogenic
CADD
Uncertain
DANN
Uncertain
DEOGEN2
Uncertain
D
FATHMM_MKL
Uncertain
D
LIST_S2
Benign
T
M_CAP
Pathogenic
D
MetaRNN
Benign
T
MetaSVM
Uncertain
D
MutationAssessor
Benign
L
MutationTaster
Benign
D
PrimateAI
Uncertain
T
PROVEAN
Benign
N
REVEL
Pathogenic
Sift
Benign
D
Sift4G
Benign
T
Polyphen
D
Vest4
MVP
MPC
ClinPred
T
GERP RS
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at