rs532348958

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_004840.3(ARHGEF6):​c.1190C>T​(p.Thr397Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000089 in 112,332 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.0000089 ( 0 hom., 0 hem., cov: 23)
Exomes 𝑓: 0.0 ( 0 hom. 0 hem. )
Failed GnomAD Quality Control

Consequence

ARHGEF6
NM_004840.3 missense

Scores

1
3
13

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.90
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]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.22261691).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
ARHGEF6NM_004840.3 linkuse as main transcriptc.1190C>T p.Thr397Ile missense_variant 11/22 ENST00000250617.7 NP_004831.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
ARHGEF6ENST00000250617.7 linkuse as main transcriptc.1190C>T p.Thr397Ile missense_variant 11/221 NM_004840.3 ENSP00000250617 P1Q15052-1
ARHGEF6ENST00000370622.5 linkuse as main transcriptc.728C>T p.Thr243Ile missense_variant 10/211 ENSP00000359656 Q15052-2
ARHGEF6ENST00000370620.5 linkuse as main transcriptc.728C>T p.Thr243Ile missense_variant 10/212 ENSP00000359654 Q15052-2

Frequencies

GnomAD3 genomes
AF:
0.00000890
AC:
1
AN:
112332
Hom.:
0
Cov.:
23
AF XY:
0.00
AC XY:
0
AN XY:
34492
show subpopulations
Gnomad AFR
AF:
0.0000323
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:
0.00
Gnomad OTH
AF:
0.00
GnomAD4 exome
Data not reliable, filtered out with message: AC0
AF:
0.00
AC:
0
AN:
1081865
Hom.:
0
Cov.:
27
AF XY:
0.00
AC XY:
0
AN XY:
348865
Gnomad4 AFR exome
AF:
0.00
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:
0.00
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.00000890
AC:
1
AN:
112332
Hom.:
0
Cov.:
23
AF XY:
0.00
AC XY:
0
AN XY:
34492
show subpopulations
Gnomad4 AFR
AF:
0.0000323
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:
0.00
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.00000756

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.11
BayesDel_addAF
Benign
-0.28
T
BayesDel_noAF
Benign
-0.64
CADD
Benign
18
DANN
Benign
0.96
DEOGEN2
Benign
0.25
.;.;T
FATHMM_MKL
Uncertain
0.94
D
LIST_S2
Uncertain
0.89
.;D;D
M_CAP
Pathogenic
0.49
D
MetaRNN
Benign
0.22
T;T;T
MetaSVM
Benign
-0.84
T
MutationAssessor
Benign
0.34
.;.;N
MutationTaster
Benign
0.90
D;D;D;D
PrimateAI
Uncertain
0.49
T
PROVEAN
Benign
-2.0
N;N;N
REVEL
Benign
0.068
Sift
Benign
0.40
T;T;T
Sift4G
Benign
0.36
T;T;T
Polyphen
0.16
.;.;B
Vest4
0.13
MutPred
0.35
.;.;Gain of catalytic residue at P399 (P = 0.0465);
MVP
0.66
MPC
0.31
ClinPred
0.63
D
GERP RS
5.1
Varity_R
0.32
gMVP
0.32

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: rs532348958; hg19: chrX-135770146; API