rs369955658

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM2BP4_StrongBP7

The NM_004840.3(ARHGEF6):​c.1653C>T​(p.Ala551Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000273 in 1,097,685 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. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 23)
Exomes 𝑓: 0.0000027 ( 0 hom. 0 hem. )

Consequence

ARHGEF6
NM_004840.3 synonymous

Scores

2

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.328

Publications

0 publications found
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]
ARHGEF6 Gene-Disease associations (from GenCC):
  • non-syndromic X-linked intellectual disability
    Inheritance: XL Classification: SUPPORTIVE, LIMITED, NO_KNOWN Submitted by: Orphanet, ClinGen, Illumina
  • complex neurodevelopmental disorder
    Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
  • congenital anomaly of kidney and urinary tract
    Inheritance: XL Classification: LIMITED Submitted by: Ambry Genetics
  • intellectual disability, X-linked 46
    Inheritance: XL Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae), G2P
  • X-linked intellectual disability
    Inheritance: XL Classification: LIMITED Submitted by: Ambry Genetics

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -3 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.83).
BP7
Synonymous conserved (PhyloP=-0.328 with no splicing effect.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
ARHGEF6NM_004840.3 linkc.1653C>T p.Ala551Ala synonymous_variant Exon 15 of 22 ENST00000250617.7 NP_004831.1 Q15052-1Q8N4Q3

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
ARHGEF6ENST00000250617.7 linkc.1653C>T p.Ala551Ala synonymous_variant Exon 15 of 22 1 NM_004840.3 ENSP00000250617.6 Q15052-1
ARHGEF6ENST00000370622.5 linkc.1191C>T p.Ala397Ala synonymous_variant Exon 14 of 21 1 ENSP00000359656.1 Q15052-2
ARHGEF6ENST00000370620.5 linkc.1191C>T p.Ala397Ala synonymous_variant Exon 14 of 21 2 ENSP00000359654.1 Q15052-2

Frequencies

GnomAD3 genomes
Cov.:
23
GnomAD2 exomes
AF:
0.00000545
AC:
1
AN:
183422
AF XY:
0.00
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000122
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000273
AC:
3
AN:
1097685
Hom.:
0
Cov.:
30
AF XY:
0.00
AC XY:
0
AN XY:
363065
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
26391
American (AMR)
AF:
0.00
AC:
0
AN:
35206
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
19384
East Asian (EAS)
AF:
0.00
AC:
0
AN:
30204
South Asian (SAS)
AF:
0.00
AC:
0
AN:
54136
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
40528
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
4135
European-Non Finnish (NFE)
AF:
0.00000356
AC:
3
AN:
841623
Other (OTH)
AF:
0.00
AC:
0
AN:
46078
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.475
Heterozygous variant carriers
0
1
1
2
2
3
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
GnomAD4 genome
Cov.:
23
EpiCase
AF:
0.00
EpiControl
AF:
0.0000593

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
May 28, 2015
Genetic Services Laboratory, University of Chicago
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.83
CADD
Benign
1.4
DANN
Benign
0.48
PhyloP100
-0.33
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

Other links and lift over

dbSNP: rs369955658; hg19: chrX-135762941; API