rs115243197

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -15 ACMG points: 1P and 16B. PP3BP4_StrongBP6_Very_StrongBS2

The NM_001177693.2(ARHGEF28):c.1862G>A(p.Arg621Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00697 in 1,612,418 control chromosomes in the GnomAD database, including 77 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0065 ( 8 hom., cov: 32)

Exomes 𝑓: 0.0070 ( 69 hom. )

Consequence

ARHGEF28
NM_001177693.2 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 9.56

Publications

10 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 -15 ACMG points.

PP3

Multiple lines of computational evidence support a deleterious effect 7: AlphaMissense, Cadd, Dann, Eigen, FATHMM_MKL, MutationAssessor, phyloP100way_vertebrate [when BayesDel_addAF, max_spliceai, MetaRNN, MutationTaster, PROVEAN was below the threshold]

BP4

Computational evidence support a benign effect (MetaRNN=0.0069202185).

BP6

Variant 5-73857727-G-A is Benign according to our data. Variant chr5-73857727-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 257361.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High Homozygotes in GnomAd4 at 8 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ARHGEF28	NM_001177693.2 link	c.1862G>A	p.Arg621Gln	missense_variant	Exon 15 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.1862G>A	p.Arg621Gln	missense_variant	Exon 15 of 36	5	NM_001177693.2	ENSP00000441436.1		Q8N1W1-1

Frequencies

GnomAD3 genomes

AF:

0.00648

AC:

985

AN:

152004

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00143

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00407

Gnomad ASJ

AF:

0.00115

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00414

Gnomad FIN

AF:

0.0355

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00668

Gnomad OTH

AF:

0.00527

GnomAD2 exomes

AF:

0.00680

AC:

1682

AN:

247172

AF XY:

0.00710

show subpopulations

Gnomad AFR exome

AF:

0.00169

Gnomad AMR exome

AF:

0.00198

Gnomad ASJ exome

AF:

0.00120

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0311

Gnomad NFE exome

AF:

0.00670

Gnomad OTH exome

AF:

0.00587

GnomAD4 exome

AF:

0.00702

AC:

10246

AN:

1460296

Hom.:

Cov.:

AF XY:

0.00694

AC XY:

5038

AN XY:

726350

show subpopulations

African (AFR)

AF:

0.00129

AC:

AN:

33432

American (AMR)

AF:

0.00215

AC:

AN:

44628

Ashkenazi Jewish (ASJ)

AF:

0.000958

AC:

AN:

26092

East Asian (EAS)

AF:

0.0000505

AC:

AN:

39580

South Asian (SAS)

AF:

0.00408

AC:

351

AN:

86032

European-Finnish (FIN)

AF:

0.0286

AC:

1523

AN:

53310

Middle Eastern (MID)

AF:

0.00122

AC:

AN:

5754

European-Non Finnish (NFE)

AF:

0.00708

AC:

7872

AN:

1111166

Other (OTH)

AF:

0.00542

AC:

327

AN:

60302

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.456

Heterozygous variant carriers

498

997

1495

1994

2492

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

306

612

918

1224

1530

<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:

0.00648

AC:

985

AN:

152122

Hom.:

Cov.:

AF XY:

0.00800

AC XY:

595

AN XY:

74372

show subpopulations

African (AFR)

AF:

0.00142

AC:

AN:

41510

American (AMR)

AF:

0.00406

AC:

AN:

15270

Ashkenazi Jewish (ASJ)

AF:

0.00115

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5182

South Asian (SAS)

AF:

0.00415

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.0355

AC:

375

AN:

10570

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.00668

AC:

454

AN:

67984

Other (OTH)

AF:

0.00521

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

137

183

229

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.00608

Hom.:

Bravo

AF:

0.00404

TwinsUK

AF:

0.00593

AC:

ALSPAC

AF:

0.00415

AC:

ESP6500AA

AF:

0.00109

AC:

ESP6500EA

AF:

0.00808

AC:

ExAC

AF:

0.00667

AC:

805

Asia WGS

AF:

0.000866

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Jan 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

ARHGEF28: BS2 -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Dec 31, 2019

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:1

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.92

BayesDel_addAF

Benign

-0.11

BayesDel_noAF

Uncertain

0.070

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.14

.;.;T;.;T;.

Eigen

Pathogenic

0.76

Eigen_PC

Pathogenic

0.79

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Pathogenic

0.99

D;D;D;.;.;D

MetaRNN

Benign

0.0069

T;T;T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Pathogenic

3.2

M;M;M;M;M;.

PhyloP100

9.6

PrimateAI

Uncertain

0.65

PROVEAN

Benign

-2.2

N;N;N;N;N;N

REVEL

Uncertain

0.36

Sift

Pathogenic

0.0

D;D;D;D;D;D

Sift4G

Pathogenic

0.0

D;D;D;D;D;D

Polyphen

1.0

D;.;D;.;D;.

Vest4

0.64

MVP

0.43

MPC

0.45

ClinPred

0.053

GERP RS

5.5

Varity_R

0.30

gMVP

0.64

Mutation Taster

=96/4

polymorphism

(source)

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

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

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