rs768494805

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001354046.2(ARHGEF7):​c.254C>A​(p.Thr85Lys) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.000000691 in 1,447,096 control chromosomes in the GnomAD database, with no homozygous occurrence. 2/3 splice prediction tools predicting alterations to normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T85M) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)
Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

ARHGEF7
NM_001354046.2 missense, splice_region

Scores

3
9
7
Splicing: ADA: 0.9924
2

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 6.71
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]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
ARHGEF7NM_001354046.2 linkc.254C>A p.Thr85Lys missense_variant, splice_region_variant Exon 3 of 22 ENST00000646102.2 NP_001340975.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
ARHGEF7ENST00000646102.2 linkc.254C>A p.Thr85Lys missense_variant, splice_region_variant Exon 3 of 22 NM_001354046.2 ENSP00000495631.1 A0A2R8YG42

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
AF:
6.91e-7
AC:
1
AN:
1447096
Hom.:
0
Cov.:
30
AF XY:
0.00
AC XY:
0
AN XY:
719828
show subpopulations
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:
9.02e-7
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
0.43
BayesDel_addAF
Pathogenic
0.31
D
BayesDel_noAF
Pathogenic
0.20
CADD
Pathogenic
28
DANN
Uncertain
0.98
DEOGEN2
Benign
0.36
.;.;T;.;T
Eigen
Uncertain
0.60
Eigen_PC
Uncertain
0.66
FATHMM_MKL
Uncertain
0.94
D
LIST_S2
Benign
0.56
T;T;T;T;T
M_CAP
Uncertain
0.12
D
MetaRNN
Uncertain
0.50
T;D;D;T;T
MetaSVM
Pathogenic
0.83
D
MutationAssessor
Uncertain
2.6
.;.;M;.;.
PrimateAI
Uncertain
0.62
T
PROVEAN
Benign
-0.80
N;N;N;.;N
REVEL
Benign
0.23
Sift
Benign
0.10
T;T;T;.;D
Sift4G
Benign
0.26
T;T;T;.;T
Polyphen
0.90
P;D;P;.;.
Vest4
0.58
MutPred
0.52
.;.;Gain of ubiquitination at T106 (P = 0.0211);.;.;
MVP
0.82
MPC
1.7
ClinPred
0.83
D
GERP RS
5.7
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.16
gMVP
0.61

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
0.99
dbscSNV1_RF
Pathogenic
0.74
SpliceAI score (max)
0.21
Details are displayed if max score is > 0.2
DS_AL_spliceai
0.21
Position offset: -1

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr13-111857637; API