Variant 12-57614038-C-T details in Genebe, Genetics Data Aggregator

Variant summary

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

The ENST00000286494.9(ARHGEF25):c.575C>T(p.Ala192Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000211 in 1,614,020 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 (★).

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000021 ( 0 hom. )

Consequence

ARHGEF25
ENST00000286494.9 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.111

Variant links:

Genes affected

ARHGEF25 (HGNC:30275): (Rho guanine nucleotide exchange factor 25) Rho GTPases alternate between an inactive GDP-bound state and an active GTP-bound state, and GEFs facilitate GDP/GTP exchange. This gene encodes a guanine nucleotide exchange factor (GEF) which interacts with Rho GTPases involved in contraction of vascular smooth muscles, regulation of responses to angiotensin II and lens cell differentiation. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jan 2012]

ARHGEF25 links:

(HGNC:):

links:

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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=0.09018162).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
ARHGEF25	NM_182947.4 linkuse as main transcript	c.575C>T	p.Ala192Val	missense_variant	6/15	ENST00000286494.9	NP_891992.3
ARHGEF25	NM_001111270.3 linkuse as main transcript	c.692C>T	p.Ala231Val	missense_variant	7/16		NP_001104740.2
ARHGEF25	NM_001347933.2 linkuse as main transcript	c.575C>T	p.Ala192Val	missense_variant	6/14		NP_001334862.2
ARHGEF25	NR_046223.2 linkuse as main transcript	n.1065C>T		non_coding_transcript_exon_variant	7/16

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ARHGEF25	ENST00000286494.9 linkuse as main transcript	c.575C>T	p.Ala192Val	missense_variant	6/15	1	NM_182947.4	ENSP00000286494	A1	Q86VW2-1
	ENST00000356672.3 linkuse as main transcript	n.764-329G>A		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152128

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.0000294

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.0000159

AC:

AN:

251484

Hom.:

AF XY:

0.0000147

AC XY:

AN XY:

135912

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:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000352

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000212

AC:

AN:

1461892

Hom.:

Cov.:

AF XY:

0.0000165

AC XY:

AN XY:

727248

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:

0.0000270

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152128

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74296

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.000478

Alfa

AF:

0.0000709

Hom.:

Bravo

AF:

0.0000227

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.00000824

AC:

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 submitter

clinical testing

Ambry Genetics

Mar 17, 2023

The c.692C>T (p.A231V) alteration is located in exon 7 (coding exon 7) of the ARHGEF25 gene. This alteration results from a C to T substitution at nucleotide position 692, causing the alanine (A) at amino acid position 231 to be replaced by a valine (V). 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

0.091

BayesDel_addAF

Benign

-0.33

BayesDel_noAF

Benign

-0.60

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.011

.;T;.

Eigen

Benign

-0.37

Eigen_PC

Benign

-0.26

FATHMM_MKL

Benign

0.16

LIST_S2

Benign

0.82

T;T;T

M_CAP

Benign

0.0071

MetaRNN

Benign

0.090

T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.8

.;L;.

MutationTaster

Benign

1.0

N;N

PrimateAI

Benign

0.38

PROVEAN

Benign

-0.74

N;N;.

REVEL

Benign

0.071

Sift

Benign

0.24

T;T;.

Sift4G

Benign

0.17

T;T;T

Polyphen

0.0070

.;B;.

Vest4

0.18

MVP

0.31

MPC

0.22

ClinPred

0.17

GERP RS

3.9

Varity_R

0.11

gMVP

0.21

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