rs7714670

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001177693.2(ARHGEF28):c.673T>C(p.Trp225Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.447 in 1,608,154 control chromosomes in the GnomAD database, including 162,170 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.42 ( 13489 hom., cov: 31)

Exomes 𝑓: 0.45 ( 148681 hom. )

Consequence

ARHGEF28
NM_001177693.2 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 0.243

Publications

39 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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=1.5380979E-4).

BP6

Variant 5-73776529-T-C is Benign according to our data. Variant chr5-73776529-T-C is described in ClinVar as Benign. ClinVar VariationId is 257376.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.452 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ARHGEF28	NM_001177693.2 link	c.673T>C	p.Trp225Arg	missense_variant	Exon 6 of 36	ENST00000513042.7	NP_001171164.1	Q8N1W1-1
ARHGEF28	NM_001080479.3 link	c.673T>C	p.Trp225Arg	missense_variant	Exon 6 of 37		NP_001073948.2	Q8N1W1-6
ARHGEF28	NM_001388078.1 link	c.673T>C	p.Trp225Arg	missense_variant	Exon 6 of 35		NP_001375007.1
ARHGEF28	NM_001388076.1 link	c.379T>C	p.Trp127Arg	missense_variant	Exon 5 of 35		NP_001375005.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ARHGEF28	ENST00000513042.7 link	c.673T>C	p.Trp225Arg	missense_variant	Exon 6 of 36	5	NM_001177693.2	ENSP00000441436.1		Q8N1W1-1

Frequencies

GnomAD3 genomes

AF:

0.418

AC:

63519

AN:

151794

Hom.:

13485

Cov.:

show subpopulations

Gnomad AFR

AF:

0.364

Gnomad AMI

AF:

0.571

Gnomad AMR

AF:

0.404

Gnomad ASJ

AF:

0.376

Gnomad EAS

AF:

0.329

Gnomad SAS

AF:

0.393

Gnomad FIN

AF:

0.469

Gnomad MID

AF:

0.418

Gnomad NFE

AF:

0.456

Gnomad OTH

AF:

0.411

GnomAD2 exomes

AF:

0.427

AC:

105730

AN:

247566

AF XY:

0.426

show subpopulations

Gnomad AFR exome

AF:

0.363

Gnomad AMR exome

AF:

0.426

Gnomad ASJ exome

AF:

0.389

Gnomad EAS exome

AF:

0.330

Gnomad FIN exome

AF:

0.471

Gnomad NFE exome

AF:

0.459

Gnomad OTH exome

AF:

0.422

GnomAD4 exome

AF:

0.450

AC:

655056

AN:

1456240

Hom.:

148681

Cov.:

AF XY:

0.448

AC XY:

324548

AN XY:

724436

show subpopulations

African (AFR)

AF:

0.356

AC:

11880

AN:

33398

American (AMR)

AF:

0.420

AC:

18651

AN:

44370

Ashkenazi Jewish (ASJ)

AF:

0.383

AC:

9940

AN:

25940

East Asian (EAS)

AF:

0.305

AC:

12088

AN:

39648

South Asian (SAS)

AF:

0.388

AC:

33089

AN:

85378

European-Finnish (FIN)

AF:

0.472

AC:

25091

AN:

53176

Middle Eastern (MID)

AF:

0.390

AC:

2237

AN:

5738

European-Non Finnish (NFE)

AF:

0.466

AC:

516023

AN:

1108502

Other (OTH)

AF:

0.434

AC:

26057

AN:

60090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.476

Heterozygous variant carriers

17080

34160

51239

68319

85399

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

15418

30836

46254

61672

77090

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.418

AC:

63553

AN:

151914

Hom.:

13489

Cov.:

AF XY:

0.418

AC XY:

31028

AN XY:

74226

show subpopulations

African (AFR)

AF:

0.364

AC:

15076

AN:

41430

American (AMR)

AF:

0.404

AC:

6173

AN:

15262

Ashkenazi Jewish (ASJ)

AF:

0.376

AC:

1304

AN:

3466

East Asian (EAS)

AF:

0.328

AC:

1691

AN:

5162

South Asian (SAS)

AF:

0.393

AC:

1885

AN:

4800

European-Finnish (FIN)

AF:

0.469

AC:

4941

AN:

10534

Middle Eastern (MID)

AF:

0.415

AC:

122

AN:

294

European-Non Finnish (NFE)

AF:

0.456

AC:

30966

AN:

67944

Other (OTH)

AF:

0.414

AC:

874

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

1843

3687

5530

7374

9217

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

616

1232

1848

2464

3080

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.440

Hom.:

70248

Bravo

AF:

0.413

TwinsUK

AF:

0.473

AC:

1754

ALSPAC

AF:

0.476

AC:

1835

ESP6500AA

AF:

0.359

AC:

1467

ESP6500EA

AF:

0.452

AC:

3811

ExAC

AF:

0.427

AC:

51645

Asia WGS

AF:

0.337

AC:

1175

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

Clinical Genetics, Academic Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

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

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Jun 09, 2021

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.069

BayesDel_addAF

Benign

-0.80

BayesDel_noAF

Benign

-0.78

CADD

Benign

(source)

DANN

Benign

0.46

DEOGEN2

Benign

0.0023

.;.;T;.;T

Eigen

Benign

-1.6

Eigen_PC

Benign

-1.5

FATHMM_MKL

Benign

0.0053

LIST_S2

Benign

0.45

T;T;T;.;.

MetaRNN

Benign

0.00015

T;T;T;T;T

MetaSVM

Benign

-0.95

MutationAssessor

Benign

-1.8

N;N;N;N;N

PhyloP100

0.24

PrimateAI

Benign

0.20

PROVEAN

Benign

0.51

N;N;N;N;N

REVEL

Benign

0.014

Sift

Benign

0.88

T;T;T;T;T

Sift4G

Benign

0.91

T;T;T;T;T

Polyphen

0.0

B;.;B;.;B

Vest4

0.035

MutPred

0.32

Gain of disorder (P = 9e-04);Gain of disorder (P = 9e-04);Gain of disorder (P = 9e-04);Gain of disorder (P = 9e-04);Gain of disorder (P = 9e-04);

MPC

0.12

ClinPred

0.00098

GERP RS

0.82

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.059

gMVP

0.26

Mutation Taster

=99/1

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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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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