13-111209994-C-T

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4BS2

The NM_001354048.1(ARHGEF7):​c.-12C>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000688 in 1,614,098 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 0.000053 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000070 ( 0 hom. )

Consequence

ARHGEF7
NM_001354048.1 5_prime_UTR_premature_start_codon_gain

Scores

4
9
6

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.56
Variant links:
Genes affected
ARHGEF7 (HGNC:15607): (Rho guanine nucleotide exchange factor 7) This gene encodes a protein that belongs to a family of cytoplasmic proteins that activate the Ras-like family of Rho proteins by exchanging bound GDP for GTP. It forms a complex with the small GTP binding protein Rac1 and recruits Rac1 to membrane ruffles and to focal adhesions. Multiple alternatively spliced transcript variants encoding different isoforms have been observed for this gene. [provided by RefSeq, Mar 2016]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -5 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.3025291).
BS2
High AC in GnomAd4 at 8 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
ARHGEF7NM_001354046.2 linkuse as main transcriptc.460C>T p.Arg154Trp missense_variant 4/22 ENST00000646102.2 NP_001340975.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
ARHGEF7ENST00000646102.2 linkuse as main transcriptc.460C>T p.Arg154Trp missense_variant 4/22 NM_001354046.2 ENSP00000495631.1 A0A2R8YG42

Frequencies

GnomAD3 genomes
AF:
0.0000526
AC:
8
AN:
152116
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.0000483
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000654
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:
0.0000735
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000517
AC:
13
AN:
251462
Hom.:
0
AF XY:
0.0000515
AC XY:
7
AN XY:
135904
show subpopulations
Gnomad AFR exome
AF:
0.0000615
Gnomad AMR exome
AF:
0.000116
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.0000980
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000440
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000705
AC:
103
AN:
1461864
Hom.:
0
Cov.:
31
AF XY:
0.0000564
AC XY:
41
AN XY:
727236
show subpopulations
Gnomad4 AFR exome
AF:
0.0000299
Gnomad4 AMR exome
AF:
0.0000894
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000252
Gnomad4 SAS exome
AF:
0.0000348
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000755
Gnomad4 OTH exome
AF:
0.000166
GnomAD4 genome
AF:
0.0000526
AC:
8
AN:
152234
Hom.:
0
Cov.:
33
AF XY:
0.0000403
AC XY:
3
AN XY:
74422
show subpopulations
Gnomad4 AFR
AF:
0.0000481
Gnomad4 AMR
AF:
0.0000654
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000735
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000512
Hom.:
0
Bravo
AF:
0.0000642
ExAC
AF:
0.0000741
AC:
9
EpiCase
AF:
0.000164
EpiControl
AF:
0.000237

ClinVar

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

Submissions by phenotype

not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsMar 29, 2022The c.523C>T (p.R175W) alteration is located in exon 5 (coding exon 5) of the ARHGEF7 gene. This alteration results from a C to T substitution at nucleotide position 523, causing the arginine (R) at amino acid position 175 to be replaced by a tryptophan (W). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.80
BayesDel_addAF
Uncertain
0.12
D
BayesDel_noAF
Pathogenic
0.14
CADD
Uncertain
25
DANN
Pathogenic
1.0
DEOGEN2
Benign
0.41
.;.;T;.;T
Eigen
Uncertain
0.56
Eigen_PC
Uncertain
0.58
FATHMM_MKL
Uncertain
0.93
D
LIST_S2
Pathogenic
0.99
D;D;D;D;D
M_CAP
Benign
0.026
D
MetaRNN
Benign
0.30
T;T;T;T;T
MetaSVM
Benign
-0.68
T
MutationAssessor
Uncertain
2.2
.;.;M;.;.
PrimateAI
Uncertain
0.71
T
PROVEAN
Uncertain
-2.5
N;N;N;.;D
REVEL
Benign
0.20
Sift
Uncertain
0.0040
D;D;D;.;D
Sift4G
Uncertain
0.0020
D;D;D;.;D
Polyphen
1.0
D;D;D;.;.
Vest4
0.86
MVP
0.72
MPC
1.5
ClinPred
0.32
T
GERP RS
5.4
Varity_R
0.39
gMVP
0.73

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: rs200107407; hg19: chr13-111862341; API