1-3463506-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_014448.4(ARHGEF16):​c.422C>T​(p.Pro141Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000119 in 1,341,928 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)
Exomes 𝑓: 0.000012 ( 0 hom. )

Consequence

ARHGEF16
NM_014448.4 missense

Scores

1
18

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.38
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 Likely_benign. Variant got -2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.05493012).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
ARHGEF16NM_014448.4 linkc.422C>T p.Pro141Leu missense_variant Exon 2 of 15 ENST00000378378.9 NP_055263.2 Q5VV41-1B3KTS4
ARHGEF16XM_017001049.2 linkc.473C>T p.Pro158Leu missense_variant Exon 2 of 15 XP_016856538.1
ARHGEF16XM_017001051.2 linkc.422C>T p.Pro141Leu missense_variant Exon 2 of 15 XP_016856540.1 Q5VV41-1
ARHGEF16XM_047418009.1 linkc.473C>T p.Pro158Leu 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.422C>T p.Pro141Leu missense_variant Exon 2 of 15 2 NM_014448.4 ENSP00000367629.4 Q5VV41-1

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD3 exomes
AF:
0.0000375
AC:
4
AN:
106558
Hom.:
0
AF XY:
0.0000718
AC XY:
4
AN XY:
55706
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 SAS exome
AF:
0.000292
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000119
AC:
16
AN:
1341928
Hom.:
0
Cov.:
31
AF XY:
0.0000213
AC XY:
14
AN XY:
655998
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:
0.000225
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
33
ExAC
AF:
0.000104
AC:
3
Asia WGS
AF:
0.000289
AC:
1
AN:
3478

ClinVar

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

Submissions by phenotype

not specified Uncertain:1
Sep 11, 2024
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.422C>T (p.P141L) 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 422, causing the proline (P) at amino acid position 141 to be replaced by a leucine (L). 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
0.078
BayesDel_addAF
Benign
-0.43
T
BayesDel_noAF
Benign
-0.56
CADD
Benign
13
DANN
Benign
0.81
DEOGEN2
Benign
0.038
T
Eigen
Benign
-0.69
Eigen_PC
Benign
-0.71
FATHMM_MKL
Benign
0.20
N
LIST_S2
Benign
0.69
T
M_CAP
Benign
0.067
D
MetaRNN
Benign
0.055
T
MetaSVM
Benign
-0.84
T
MutationAssessor
Benign
1.6
L
PrimateAI
Benign
0.32
T
PROVEAN
Benign
-1.2
N
REVEL
Benign
0.097
Sift
Benign
0.053
T
Sift4G
Uncertain
0.055
T
Polyphen
0.0
B
Vest4
0.13
MutPred
0.19
Gain of MoRF binding (P = 0.0561);
MVP
0.51
MPC
0.24
ClinPred
0.050
T
GERP RS
3.8
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.1
Varity_R
0.067
gMVP
0.17

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: rs753171238; hg19: chr1-3380070; COSMIC: COSV65682880; COSMIC: COSV65682880; API