Variant 7-144364173-G-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4_StrongBP6

The NM_005435.4(ARHGEF5):c.1504G>T(p.Val502Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 16/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00024 ( 0 hom., cov: 3)

Exomes 𝑓: 0.00080 ( 133 hom. )

Failed GnomAD Quality Control

Consequence

ARHGEF5
NM_005435.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:1

Conservation

PhyloP100: -0.694

Variant links:

Genes affected

ARHGEF5 (HGNC:13209): (Rho guanine nucleotide exchange factor 5) Rho GTPases play a fundamental role in numerous cellular processes initiated by extracellular stimuli that work through G protein coupled receptors. The encoded protein may form a complex with G proteins and stimulate Rho-dependent signals. This protein may be involved in the control of cytoskeletal organization. [provided by RefSeq, Jul 2008]

ARHGEF5 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -5 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.015350014).

BP6

Variant 7-144364173-G-T is Benign according to our data. Variant chr7-144364173-G-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 2658128.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ARHGEF5	NM_005435.4 linkuse as main transcript	c.1504G>T	p.Val502Leu	missense_variant	2/15	ENST00000056217.10	NP_005426.2
ARHGEF5	XM_017012623.3 linkuse as main transcript	c.1504G>T	p.Val502Leu	missense_variant	2/6		XP_016868112.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ARHGEF5	ENST00000056217.10 linkuse as main transcript	c.1504G>T	p.Val502Leu	missense_variant	2/15	1	NM_005435.4	ENSP00000056217	P1	Q12774-1
ARHGEF5	ENST00000498580.5 linkuse as main transcript	c.184+1320G>T		intron_variant		3		ENSP00000417979

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

AN:

49410

Hom.:

Cov.:

FAILED QC

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:

0.000555

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000693

AC:

AN:

115512

Hom.:

AF XY:

0.000694

AC XY:

AN XY:

61980

show subpopulations

Gnomad AFR exome

AF:

0.000248

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000211

Gnomad SAS exome

AF:

0.000310

Gnomad FIN exome

AF:

0.000872

Gnomad NFE exome

AF:

0.00134

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.000795

AC:

558

AN:

701540

Hom.:

133

Cov.:

AF XY:

0.000806

AC XY:

286

AN XY:

355050

show subpopulations

Gnomad4 AFR exome

AF:

0.000106

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000384

Gnomad4 SAS exome

AF:

0.000840

Gnomad4 FIN exome

AF:

0.00131

Gnomad4 NFE exome

AF:

0.000919

Gnomad4 OTH exome

AF:

0.000419

GnomAD4 genome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.000243

AC:

AN:

49438

Hom.:

Cov.:

AF XY:

0.000208

AC XY:

AN XY:

24084

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:

0.000555

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000298

Hom.:

ExAC

AF:

0.000939

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 10, 2022

The c.1504G>T (p.V502L) alteration is located in exon 2 (coding exon 1) of the ARHGEF5 gene. This alteration results from a G to T substitution at nucleotide position 1504, causing the valine (V) at amino acid position 502 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Nov 01, 2022

ARHGEF5: BP4, BS2 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.20

BayesDel_addAF

Benign

-0.27

BayesDel_noAF

Benign

-0.63

CADD

Benign

0.33

DANN

Benign

0.70

DEOGEN2

Benign

0.066

Eigen

Benign

-1.5

Eigen_PC

Benign

-1.6

FATHMM_MKL

Benign

0.053

LIST_S2

Benign

0.26

M_CAP

Benign

0.012

MetaRNN

Benign

0.015

MetaSVM

Benign

-0.95

MutationAssessor

Benign

1.4

MutationTaster

Benign

1.0

PrimateAI

Benign

0.24

PROVEAN

Benign

-0.68

REVEL

Benign

0.097

Sift

Benign

0.13

Sift4G

Benign

0.33

Polyphen

0.0

Vest4

0.044

MutPred

0.23

Loss of sheet (P = 0.0817);

MVP

0.48

ClinPred

0.0020

GERP RS

-8.0

Varity_R

0.047

gMVP

0.074

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