1-3463136-C-T

Variant summary

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

The NM_014448.4(ARHGEF16):​c.52C>T​(p.Arg18Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000296 in 1,484,362 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R18H) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00011 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000021 ( 0 hom. )

Consequence

ARHGEF16
NM_014448.4 missense

Scores

1
5
13

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.24
Variant links:
Genes affected
ARHGEF16 (HGNC:15515): (Rho guanine nucleotide exchange factor 16) Although the specific function of this protein is not known yet, it is thought to be involved in protein-protein and protein-lipid interactions. [provided by RefSeq, Jul 2008]

Genome browser will be placed here

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=0.117826164).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
ARHGEF16NM_014448.4 linkc.52C>T p.Arg18Cys missense_variant Exon 2 of 15 ENST00000378378.9 NP_055263.2 Q5VV41-1B3KTS4
ARHGEF16XM_017001049.2 linkc.103C>T p.Arg35Cys missense_variant Exon 2 of 15 XP_016856538.1
ARHGEF16XM_017001051.2 linkc.52C>T p.Arg18Cys missense_variant Exon 2 of 15 XP_016856540.1 Q5VV41-1
ARHGEF16XM_047418009.1 linkc.103C>T p.Arg35Cys missense_variant Exon 2 of 8 XP_047273965.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
ARHGEF16ENST00000378378.9 linkc.52C>T p.Arg18Cys missense_variant Exon 2 of 15 2 NM_014448.4 ENSP00000367629.4 Q5VV41-1

Frequencies

GnomAD3 genomes
AF:
0.000105
AC:
16
AN:
152140
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.000121
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000654
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.000207
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.000140
AC:
15
AN:
107022
Hom.:
0
AF XY:
0.000163
AC XY:
9
AN XY:
55122
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.000883
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000210
AC:
28
AN:
1332106
Hom.:
0
Cov.:
31
AF XY:
0.0000262
AC XY:
17
AN XY:
649050
show subpopulations
Gnomad4 AFR exome
AF:
0.000238
Gnomad4 AMR exome
AF:
0.000592
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000429
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000192
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.000105
AC:
16
AN:
152256
Hom.:
0
Cov.:
33
AF XY:
0.000161
AC XY:
12
AN XY:
74436
show subpopulations
Gnomad4 AFR
AF:
0.000120
Gnomad4 AMR
AF:
0.000653
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.000207
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.0000945

ClinVar

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

Submissions by phenotype

not specified Uncertain:1
Jun 21, 2023
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.52C>T (p.R18C) alteration is located in exon 2 (coding exon 1) of the ARHGEF16 gene. This alteration results from a C to T substitution at nucleotide position 52, causing the arginine (R) at amino acid position 18 to be replaced by a cysteine (C). 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
Benign
0.10
BayesDel_addAF
Benign
-0.33
T
BayesDel_noAF
Benign
-0.33
CADD
Uncertain
25
DANN
Uncertain
1.0
DEOGEN2
Benign
0.063
T
Eigen
Benign
-0.038
Eigen_PC
Benign
-0.13
FATHMM_MKL
Benign
0.38
N
LIST_S2
Uncertain
0.89
D
M_CAP
Benign
0.075
D
MetaRNN
Benign
0.12
T
MetaSVM
Benign
-0.97
T
MutationAssessor
Uncertain
2.4
M
PrimateAI
Uncertain
0.78
T
PROVEAN
Benign
-1.4
N
REVEL
Benign
0.15
Sift
Uncertain
0.0010
D
Sift4G
Pathogenic
0.0010
D
Polyphen
1.0
D
Vest4
0.31
MutPred
0.39
Loss of phosphorylation at S21 (P = 0.0531);
MVP
0.32
MPC
0.96
ClinPred
0.13
T
GERP RS
3.6
Varity_R
0.19
gMVP
0.33

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: rs942176075; hg19: chr1-3379700; API