rs61734875

Variant names:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_001177693.2(ARHGEF28):c.3294T>C(p.Ala1098Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0464 in 1,612,504 control chromosomes in the GnomAD database, including 2,056 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.036 ( 174 hom., cov: 32)

Exomes 𝑓: 0.047 ( 1882 hom. )

Consequence

ARHGEF28
NM_001177693.2 synonymous

Scores

Clinical Significance

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

Conservation

PhyloP100: -1.76

Publications

4 publications found

Variant links:

COSMIC-nc: COSV104382973

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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.78).

BP6

Variant 5-73886088-T-C is Benign according to our data. Variant chr5-73886088-T-C is described in ClinVar as Benign. ClinVar VariationId is 257368.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-1.76 with no splicing effect.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0509 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ARHGEF28	NM_001177693.2 link	c.3294T>C	p.Ala1098Ala	synonymous_variant	Exon 25 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.3294T>C	p.Ala1098Ala	synonymous_variant	Exon 25 of 36	5	NM_001177693.2	ENSP00000441436.1		Q8N1W1-1

Frequencies

GnomAD3 genomes

AF:

0.0365

AC:

5558

AN:

152186

Hom.:

174

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00837

Gnomad AMI

AF:

0.0330

Gnomad AMR

AF:

0.0331

Gnomad ASJ

AF:

0.117

Gnomad EAS

AF:

0.000578

Gnomad SAS

AF:

0.0112

Gnomad FIN

AF:

0.0521

Gnomad MID

AF:

0.0285

Gnomad NFE

AF:

0.0524

Gnomad OTH

AF:

0.0425

GnomAD2 exomes

AF:

0.0389

AC:

9642

AN:

248030

AF XY:

0.0392

show subpopulations

Gnomad AFR exome

AF:

0.00717

Gnomad AMR exome

AF:

0.0214

Gnomad ASJ exome

AF:

0.120

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0513

Gnomad NFE exome

AF:

0.0522

Gnomad OTH exome

AF:

0.0434

GnomAD4 exome

AF:

0.0474

AC:

69269

AN:

1460200

Hom.:

1882

Cov.:

AF XY:

0.0464

AC XY:

33708

AN XY:

726202

show subpopulations

African (AFR)

AF:

0.00782

AC:

261

AN:

33388

American (AMR)

AF:

0.0225

AC:

1002

AN:

44564

Ashkenazi Jewish (ASJ)

AF:

0.117

AC:

3041

AN:

26064

East Asian (EAS)

AF:

0.000101

AC:

AN:

39674

South Asian (SAS)

AF:

0.0118

AC:

1015

AN:

85890

European-Finnish (FIN)

AF:

0.0515

AC:

2752

AN:

53386

Middle Eastern (MID)

AF:

0.0309

AC:

178

AN:

5758

European-Non Finnish (NFE)

AF:

0.0525

AC:

58302

AN:

1111146

Other (OTH)

AF:

0.0450

AC:

2714

AN:

60330

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.474

Heterozygous variant carriers

3406

6812

10218

13624

17030

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

2124

4248

6372

8496

10620

<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:

0.0365

AC:

5557

AN:

152304

Hom.:

174

Cov.:

AF XY:

0.0362

AC XY:

2693

AN XY:

74472

show subpopulations

African (AFR)

AF:

0.00834

AC:

347

AN:

41582

American (AMR)

AF:

0.0330

AC:

505

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.117

AC:

405

AN:

3472

East Asian (EAS)

AF:

0.000579

AC:

AN:

5180

South Asian (SAS)

AF:

0.0114

AC:

AN:

4816

European-Finnish (FIN)

AF:

0.0521

AC:

553

AN:

10618

Middle Eastern (MID)

AF:

0.0272

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0524

AC:

3562

AN:

68026

Other (OTH)

AF:

0.0421

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

273

546

820

1093

1366

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

128

192

256

320

<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:

0.0472

Hom.:

165

Bravo

AF:

0.0343

Asia WGS

AF:

0.00751

AC:

AN:

3478

EpiCase

AF:

0.0524

EpiControl

AF:

0.0542

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Apr 18, 2016

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

- -

not provided

Benign:3

Jun 10, 2021

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance:Likely benign

Review Status:no assertion criteria provided

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

BayesDel_noAF

Benign

-0.78

CADD

Benign

0.68

(source)

DANN

Benign

0.58

PhyloP100

-1.8

PromoterAI

0.015

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Mutation Taster

=99/1

polymorphism (auto)

(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