Variant 14-21074607-A-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_018071.5(ARHGEF40):c.877A>G(p.Lys293Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.156 in 1,567,194 control chromosomes in the GnomAD database, including 21,673 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.13 ( 1836 hom., cov: 32)

Exomes 𝑓: 0.16 ( 19837 hom. )

Consequence

ARHGEF40
NM_018071.5 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 1.65

Variant links:

Genes affected

ARHGEF40 (HGNC:25516): (Rho guanine nucleotide exchange factor 40) This gene encodes a protein similar to guanosine nucleotide exchange factors for Rho GTPases. The encoded protein contains in its C-terminus a GEF domain involved in exchange activity and a pleckstrin homology domain. Alternatively spliced transcripts that encode different proteins have been described. [provided by RefSeq, Mar 2014]

ARHGEF40 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.004220277).

BP6

Variant 14-21074607-A-G is Benign according to our data. Variant chr14-21074607-A-G is described in ClinVar as [Benign]. Clinvar id is 1298043.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.271 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ARHGEF40	NM_018071.5 link	c.877A>G	p.Lys293Glu	missense_variant	3/24	ENST00000298694.9	NP_060541.3	Q8TER5-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ARHGEF40	ENST00000298694.9 link	c.877A>G	p.Lys293Glu	missense_variant	3/24	2	NM_018071.5	ENSP00000298694.4		Q8TER5-1

Frequencies

GnomAD3 genomes

AF:

0.128

AC:

19463

AN:

151942

Hom.:

1837

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0318

Gnomad AMI

AF:

0.0713

Gnomad AMR

AF:

0.277

Gnomad ASJ

AF:

0.107

Gnomad EAS

AF:

0.0281

Gnomad SAS

AF:

0.171

Gnomad FIN

AF:

0.113

Gnomad MID

AF:

0.0791

Gnomad NFE

AF:

0.163

Gnomad OTH

AF:

0.115

GnomAD3 exomes

AF:

0.164

AC:

29680

AN:

181004

Hom.:

3294

AF XY:

0.161

AC XY:

15747

AN XY:

97824

show subpopulations

Gnomad AFR exome

AF:

0.0268

Gnomad AMR exome

AF:

0.358

Gnomad ASJ exome

AF:

0.108

Gnomad EAS exome

AF:

0.0283

Gnomad SAS exome

AF:

0.167

Gnomad FIN exome

AF:

0.123

Gnomad NFE exome

AF:

0.158

Gnomad OTH exome

AF:

0.148

GnomAD4 exome

AF:

0.159

AC:

225662

AN:

1415136

Hom.:

19837

Cov.:

AF XY:

0.159

AC XY:

111609

AN XY:

699800

show subpopulations

Gnomad4 AFR exome

AF:

0.0243

Gnomad4 AMR exome

AF:

0.346

Gnomad4 ASJ exome

AF:

0.109

Gnomad4 EAS exome

AF:

0.0303

Gnomad4 SAS exome

AF:

0.168

Gnomad4 FIN exome

AF:

0.120

Gnomad4 NFE exome

AF:

0.166

Gnomad4 OTH exome

AF:

0.138

GnomAD4 genome

AF:

0.128

AC:

19460

AN:

152058

Hom.:

1836

Cov.:

AF XY:

0.129

AC XY:

9580

AN XY:

74338

show subpopulations

Gnomad4 AFR

AF:

0.0317

Gnomad4 AMR

AF:

0.278

Gnomad4 ASJ

AF:

0.107

Gnomad4 EAS

AF:

0.0283

Gnomad4 SAS

AF:

0.170

Gnomad4 FIN

AF:

0.113

Gnomad4 NFE

AF:

0.163

Gnomad4 OTH

AF:

0.113

Alfa

AF:

0.146

Hom.:

660

Bravo

AF:

0.133

TwinsUK

AF:

0.169

AC:

628

ALSPAC

AF:

0.177

AC:

683

ESP6500AA

AF:

0.0332

AC:

145

ESP6500EA

AF:

0.146

AC:

1243

ExAC

AF:

0.128

AC:

15097

Asia WGS

AF:

0.100

AC:

351

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 16, 2020	This variant is associated with the following publications: (PMID: 27798624) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.32

BayesDel_addAF

Benign

-0.54

BayesDel_noAF

Benign

-0.40

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.0090

T;T

Eigen

Benign

-0.025

Eigen_PC

Benign

0.0067

FATHMM_MKL

Benign

0.56

LIST_S2

Benign

0.84

T;T

MetaRNN

Benign

0.0042

T;T

MetaSVM

Benign

-0.75

MutationAssessor

Uncertain

2.2

M;.

PrimateAI

Uncertain

0.65

PROVEAN

Benign

0.070

N;N

REVEL

Benign

0.11

Sift

Uncertain

0.0050

D;D

Sift4G

Uncertain

0.021

D;D

Polyphen

0.65

P;D

Vest4

0.13

MPC

0.37

ClinPred

0.035

GERP RS

3.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.17

gMVP

0.54

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