rs188040167

Variant names:

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2

The NM_001177693.2(ARHGEF28):c.4054G>A(p.Val1352Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00392 in 1,612,966 control chromosomes in the GnomAD database, including 13 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0031 ( 1 hom., cov: 32)

Exomes 𝑓: 0.0040 ( 12 hom. )

Consequence

ARHGEF28
NM_001177693.2 missense

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 2.26

Publications

14 publications found

Variant links:

Genes affected

ARHGEF28 (HGNC:30322): (Rho guanine nucleotide exchange factor 28) This gene encodes a member of the Rho guanine nucleotide exchange factor family. The encoded protein interacts with low molecular weight neurofilament mRNA and may be involved in the formation of amyotrophic lateral sclerosis neurofilament aggregates. Alternate splicing results in multiple transcript variants.[provided by RefSeq, Apr 2010]

ARHGEF28 Gene-Disease associations (from GenCC):

amyotrophic lateral sclerosis
Inheritance: AD, AR Classification: MODERATE Submitted by: Genomics England PanelApp

ARHGEF28 links:

ENSG00000304540 (HGNC:):

ENSG00000304540 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -16 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0044407547).

BP6

Variant 5-73901264-G-A is Benign according to our data. Variant chr5-73901264-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 257370.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High Homozygotes in GnomAdExome4 at 12 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ARHGEF28	NM_001177693.2 link	c.4054G>A	p.Val1352Ile	missense_variant	Exon 31 of 36	ENST00000513042.7	NP_001171164.1	Q8N1W1-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ARHGEF28	ENST00000513042.7 link	c.4054G>A	p.Val1352Ile	missense_variant	Exon 31 of 36	5	NM_001177693.2	ENSP00000441436.1		Q8N1W1-1

Frequencies

GnomAD3 genomes

AF:

0.00314

AC:

478

AN:

152070

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000894

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00439

Gnomad ASJ

AF:

0.00519

Gnomad EAS

AF:

0.000771

Gnomad SAS

AF:

0.00228

Gnomad FIN

AF:

0.00302

Gnomad MID

AF:

0.0127

Gnomad NFE

AF:

0.00435

Gnomad OTH

AF:

0.00431

GnomAD2 exomes

AF:

0.00293

AC:

728

AN:

248556

AF XY:

0.00298

show subpopulations

Gnomad AFR exome

AF:

0.000843

Gnomad AMR exome

AF:

0.00163

Gnomad ASJ exome

AF:

0.00399

Gnomad EAS exome

AF:

0.000278

Gnomad FIN exome

AF:

0.00190

Gnomad NFE exome

AF:

0.00454

Gnomad OTH exome

AF:

0.00314

GnomAD4 exome

AF:

0.00400

AC:

5848

AN:

1460778

Hom.:

Cov.:

AF XY:

0.00399

AC XY:

2900

AN XY:

726628

show subpopulations

African (AFR)

AF:

0.000687

AC:

AN:

33470

American (AMR)

AF:

0.00141

AC:

AN:

44678

Ashkenazi Jewish (ASJ)

AF:

0.00556

AC:

145

AN:

26098

East Asian (EAS)

AF:

0.000403

AC:

AN:

39664

South Asian (SAS)

AF:

0.00187

AC:

161

AN:

86026

European-Finnish (FIN)

AF:

0.00251

AC:

134

AN:

53332

Middle Eastern (MID)

AF:

0.00226

AC:

AN:

5760

European-Non Finnish (NFE)

AF:

0.00455

AC:

5056

AN:

1111416

Other (OTH)

AF:

0.00393

AC:

237

AN:

60334

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.461

Heterozygous variant carriers

282

563

845

1126

1408

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.00314

AC:

478

AN:

152188

Hom.:

Cov.:

AF XY:

0.00332

AC XY:

247

AN XY:

74402

show subpopulations

African (AFR)

AF:

0.000892

AC:

AN:

41500

American (AMR)

AF:

0.00438

AC:

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.00519

AC:

AN:

3468

East Asian (EAS)

AF:

0.000773

AC:

AN:

5174

South Asian (SAS)

AF:

0.00229

AC:

AN:

4814

European-Finnish (FIN)

AF:

0.00302

AC:

AN:

10610

Middle Eastern (MID)

AF:

0.0136

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00435

AC:

296

AN:

68008

Other (OTH)

AF:

0.00427

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

108

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00376

Hom.:

Bravo

AF:

0.00284

TwinsUK

AF:

0.00512

AC:

ALSPAC

AF:

0.00441

AC:

ESP6500AA

AF:

0.00126

AC:

ESP6500EA

AF:

0.00494

AC:

ExAC

AF:

0.00304

AC:

367

Asia WGS

AF:

0.000866

AC:

AN:

3478

EpiCase

AF:

0.00469

EpiControl

AF:

0.00380

ClinVar

Significance: Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

Oct 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

ARHGEF28: BP4 -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Clinical Genetics, Academic Medical Center

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Dec 31, 2019

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:1

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.089

BayesDel_addAF

Benign

-0.61

BayesDel_noAF

Benign

-0.64

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.0091

.;.;T;.;T;.;T

Eigen

Benign

0.044

Eigen_PC

Benign

0.12

FATHMM_MKL

Benign

0.65

LIST_S2

Benign

0.66

T;T;T;.;.;T;T

M_CAP

Benign

0.0063

MetaRNN

Benign

0.0044

T;T;T;T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.1

M;M;M;M;M;.;.

PhyloP100

2.3

PrimateAI

Benign

0.29

PROVEAN

Benign

-0.15

N;N;N;N;N;N;N

REVEL

Benign

0.070

Sift

Benign

0.19

T;T;T;T;T;T;T

Sift4G

Benign

0.26

T;T;T;T;T;T;T

Polyphen

0.23

B;.;P;.;P;.;P

Vest4

0.11

MVP

0.20

MPC

0.063

ClinPred

0.0068

GERP RS

3.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.056

gMVP

0.058

Mutation Taster

=95/5

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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rs188040167

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over