Variant 17-8312076-A-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_173728.4(ARHGEF15):c.37A>C(p.Thr13Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict 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. T13M) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0011 ( 0 hom., cov: 16)

Exomes 𝑓: 0.00053 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

ARHGEF15
NM_173728.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.269

Variant links:

Genes affected

ARHGEF15 (HGNC:15590): (Rho guanine nucleotide exchange factor 15) Rho GTPases play a fundamental role in numerous cellular processes that are initiated by extracellular stimuli that work through G protein-coupled receptors. This gene encodes a protein that functions as a specific guanine nucleotide exchange factor for RhoA. It also interacts with ephrin A4 in vascular smooth muscle cells. Two alternatively spliced transcripts variants that encode the same protein have been found for this gene. [provided by RefSeq, Aug 2010]

ARHGEF15 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.16974118).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ARHGEF15	NM_173728.4 linkuse as main transcript	c.37A>C	p.Thr13Pro	missense_variant	2/16	ENST00000361926.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ARHGEF15	ENST00000361926.8 linkuse as main transcript	c.37A>C	p.Thr13Pro	missense_variant	2/16	1	NM_173728.4	P1

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

AN:

62216

Hom.:

Cov.:

FAILED QC

Gnomad AFR

AF:

0.00115

Gnomad AMI

AF:

0.00244

Gnomad AMR

AF:

0.000612

Gnomad ASJ

AF:

0.00191

Gnomad EAS

AF:

0.00517

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000539

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00103

Gnomad OTH

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.000527

AC:

530

AN:

1006534

Hom.:

Cov.:

AF XY:

0.000563

AC XY:

279

AN XY:

495326

show subpopulations

Gnomad4 AFR exome

AF:

0.000404

Gnomad4 AMR exome

AF:

0.00110

Gnomad4 ASJ exome

AF:

0.00121

Gnomad4 EAS exome

AF:

0.000739

Gnomad4 SAS exome

AF:

0.00202

Gnomad4 FIN exome

AF:

0.00122

Gnomad4 NFE exome

AF:

0.000362

Gnomad4 OTH exome

AF:

0.000967

GnomAD4 genome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.00109

AC:

AN:

62314

Hom.:

Cov.:

AF XY:

0.000949

AC XY:

AN XY:

30572

show subpopulations

Gnomad4 AFR

AF:

0.00115

Gnomad4 AMR

AF:

0.000611

Gnomad4 ASJ

AF:

0.00191

Gnomad4 EAS

AF:

0.00517

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000539

Gnomad4 NFE

AF:

0.00103

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.00150

Hom.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Early infantile epileptic encephalopathy with suppression bursts

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Mar 22, 2021

This sequence change replaces threonine with proline at codon 13 of the ARHGEF15 protein (p.Thr13Pro). The threonine residue is moderately conserved and there is a small physicochemical difference between threonine and proline. This variant is not present in population databases (ExAC no frequency). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals with ARHGEF15-related conditions. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.057

BayesDel_addAF

Benign

-0.038

BayesDel_noAF

Benign

-0.29

Cadd

Benign

Dann

Benign

0.93

Eigen

Benign

-0.13

Eigen_PC

Benign

-0.058

FATHMM_MKL

Benign

0.58

LIST_S2

Benign

0.59

T;.;T;T

M_CAP

Benign

0.022

MetaRNN

Benign

0.17

T;T;T;T

MetaSVM

Benign

-0.91

MutationTaster

Benign

1.0

N;N

PrimateAI

Uncertain

0.49

Sift4G

Benign

0.25

T;T;T;T

Polyphen

0.61

.;P;.;P

Vest4

0.30, 0.30

MVP

0.76

MPC

0.17

ClinPred

0.062

GERP RS

2.4

Varity_R

0.19

gMVP

0.18

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over