rs2973566

Variant names:

Your query was ambiguous. Multiple possible variants found:

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.1754G>A(p.Arg585Lys) variant causes a missense change. The variant allele was found at a frequency of 0.27 in 1,611,420 control chromosomes in the GnomAD database, including 61,846 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.23 ( 4488 hom., cov: 32)

Exomes 𝑓: 0.27 ( 57358 hom. )

Consequence

ARHGEF28
NM_001177693.2 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 6.54

Publications

28 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=0.0014189482).

BP6

Variant 5-73852656-G-A is Benign according to our data. Variant chr5-73852656-G-A is described in ClinVar as [Benign]. Clinvar id is 257360.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.285 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ARHGEF28	NM_001177693.2 link	c.1754G>A	p.Arg585Lys	missense_variant	Exon 14 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.1754G>A	p.Arg585Lys	missense_variant	Exon 14 of 36	5	NM_001177693.2	ENSP00000441436.1		Q8N1W1-1

Frequencies

GnomAD3 genomes

AF:

0.230

AC:

34874

AN:

151912

Hom.:

4488

Cov.:

show subpopulations

Gnomad AFR

AF:

0.128

Gnomad AMI

AF:

0.369

Gnomad AMR

AF:

0.277

Gnomad ASJ

AF:

0.270

Gnomad EAS

AF:

0.0702

Gnomad SAS

AF:

0.190

Gnomad FIN

AF:

0.249

Gnomad MID

AF:

0.258

Gnomad NFE

AF:

0.289

Gnomad OTH

AF:

0.226

GnomAD2 exomes

AF:

0.246

AC:

61060

AN:

248712

AF XY:

0.243

show subpopulations

Gnomad AFR exome

AF:

0.124

Gnomad AMR exome

AF:

0.310

Gnomad ASJ exome

AF:

0.274

Gnomad EAS exome

AF:

0.0635

Gnomad FIN exome

AF:

0.258

Gnomad NFE exome

AF:

0.281

Gnomad OTH exome

AF:

0.253

GnomAD4 exome

AF:

0.275

AC:

400918

AN:

1459388

Hom.:

57358

Cov.:

AF XY:

0.272

AC XY:

197413

AN XY:

726066

show subpopulations

African (AFR)

AF:

0.120

AC:

4020

AN:

33438

American (AMR)

AF:

0.303

AC:

13530

AN:

44670

Ashkenazi Jewish (ASJ)

AF:

0.269

AC:

7034

AN:

26104

East Asian (EAS)

AF:

0.0581

AC:

2306

AN:

39676

South Asian (SAS)

AF:

0.192

AC:

16504

AN:

86152

European-Finnish (FIN)

AF:

0.255

AC:

13582

AN:

53244

Middle Eastern (MID)

AF:

0.243

AC:

1400

AN:

5756

European-Non Finnish (NFE)

AF:

0.295

AC:

327039

AN:

1110028

Other (OTH)

AF:

0.257

AC:

15503

AN:

60320

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.455

Heterozygous variant carriers

13941

27882

41822

55763

69704

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.229

AC:

34884

AN:

152032

Hom.:

4488

Cov.:

AF XY:

0.225

AC XY:

16745

AN XY:

74346

show subpopulations

African (AFR)

AF:

0.128

AC:

5309

AN:

41464

American (AMR)

AF:

0.277

AC:

4230

AN:

15274

Ashkenazi Jewish (ASJ)

AF:

0.270

AC:

936

AN:

3466

East Asian (EAS)

AF:

0.0705

AC:

365

AN:

5176

South Asian (SAS)

AF:

0.191

AC:

915

AN:

4802

European-Finnish (FIN)

AF:

0.249

AC:

2631

AN:

10584

Middle Eastern (MID)

AF:

0.255

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.289

AC:

19618

AN:

67956

Other (OTH)

AF:

0.223

AC:

470

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1346

2691

4037

5382

6728

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.261

Hom.:

24618

Bravo

AF:

0.229

TwinsUK

AF:

0.304

AC:

1126

ALSPAC

AF:

0.299

AC:

1152

ESP6500AA

AF:

0.127

AC:

477

ESP6500EA

AF:

0.278

AC:

2289

ExAC

AF:

0.241

AC:

29071

Asia WGS

AF:

0.120

AC:

417

AN:

3478

EpiCase

AF:

0.278

EpiControl

AF:

0.276

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Clinical Genetics, Academic 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

- -

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

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not provided

Benign:2

Jun 09, 2021

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.55

BayesDel_noAF

Benign

-0.42

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.11

.;.;T;.;T;.

Eigen

Pathogenic

0.75

Eigen_PC

Pathogenic

0.78

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Benign

0.85

T;T;T;.;.;T

MetaRNN

Benign

0.0014

T;T;T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Uncertain

2.6

M;M;M;M;M;.

PhyloP100

6.5

PrimateAI

Uncertain

0.55

PROVEAN

Benign

-1.2

N;N;N;N;N;N

REVEL

Benign

0.14

Sift

Uncertain

0.016

D;D;D;D;D;D

Sift4G

Uncertain

0.044

D;D;D;D;D;T

Polyphen

0.99

D;.;D;.;D;.

Vest4

0.34

MPC

0.39

ClinPred

0.022

GERP RS

6.2

Varity_R

0.18

gMVP

0.47

Mutation Taster

=99/1

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

Splicevardb

2.0

SpliceAI score (max)

0.040

Details are displayed if max score is > 0.2

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

rs2973566

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