rs2973558

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.2338C>A(p.His780Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.311 in 1,607,836 control chromosomes in the GnomAD database, including 80,555 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 0.29 ( 6596 hom., cov: 32)

Exomes 𝑓: 0.31 ( 73959 hom. )

Consequence

ARHGEF28
NM_001177693.2 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: -0.160

Publications

30 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=2.4458766E-4).

BP6

Variant 5-73868140-C-A is Benign according to our data. Variant chr5-73868140-C-A is described in ClinVar as Benign. ClinVar VariationId is 257364.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.378 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ARHGEF28	NM_001177693.2 link	c.2338C>A	p.His780Asn	missense_variant	Exon 20 of 36	ENST00000513042.7	NP_001171164.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ARHGEF28	ENST00000513042.7 link	c.2338C>A	p.His780Asn	missense_variant	Exon 20 of 36	5	NM_001177693.2	ENSP00000441436.1

Frequencies

GnomAD3 genomes

AF:

0.285

AC:

43360

AN:

151954

Hom.:

6587

Cov.:

show subpopulations

Gnomad AFR

AF:

0.209

Gnomad AMI

AF:

0.321

Gnomad AMR

AF:

0.386

Gnomad ASJ

AF:

0.304

Gnomad EAS

AF:

0.138

Gnomad SAS

AF:

0.196

Gnomad FIN

AF:

0.294

Gnomad MID

AF:

0.301

Gnomad NFE

AF:

0.324

Gnomad OTH

AF:

0.284

GnomAD2 exomes

AF:

0.299

AC:

71577

AN:

239616

AF XY:

0.290

show subpopulations

Gnomad AFR exome

AF:

0.208

Gnomad AMR exome

AF:

0.460

Gnomad ASJ exome

AF:

0.299

Gnomad EAS exome

AF:

0.137

Gnomad FIN exome

AF:

0.299

Gnomad NFE exome

AF:

0.315

Gnomad OTH exome

AF:

0.294

GnomAD4 exome

AF:

0.314

AC:

457341

AN:

1455762

Hom.:

73959

Cov.:

AF XY:

0.310

AC XY:

223952

AN XY:

723452

show subpopulations

African (AFR)

AF:

0.203

AC:

6785

AN:

33438

American (AMR)

AF:

0.448

AC:

19581

AN:

43692

Ashkenazi Jewish (ASJ)

AF:

0.295

AC:

7660

AN:

25990

East Asian (EAS)

AF:

0.116

AC:

4572

AN:

39550

South Asian (SAS)

AF:

0.200

AC:

17043

AN:

85190

European-Finnish (FIN)

AF:

0.298

AC:

15825

AN:

53052

Middle Eastern (MID)

AF:

0.265

AC:

1517

AN:

5732

European-Non Finnish (NFE)

AF:

0.330

AC:

366361

AN:

1108950

Other (OTH)

AF:

0.299

AC:

17997

AN:

60168

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.469

Heterozygous variant carriers

17652

35305

52957

70610

88262

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

11922

23844

35766

47688

59610

<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:

0.285

AC:

43398

AN:

152074

Hom.:

6596

Cov.:

AF XY:

0.280

AC XY:

20850

AN XY:

74342

show subpopulations

African (AFR)

AF:

0.210

AC:

8694

AN:

41480

American (AMR)

AF:

0.387

AC:

5908

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.304

AC:

1055

AN:

3472

East Asian (EAS)

AF:

0.138

AC:

714

AN:

5176

South Asian (SAS)

AF:

0.196

AC:

945

AN:

4814

European-Finnish (FIN)

AF:

0.294

AC:

3102

AN:

10564

Middle Eastern (MID)

AF:

0.306

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.324

AC:

22005

AN:

67966

Other (OTH)

AF:

0.281

AC:

593

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1573

3147

4720

6294

7867

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

436

872

1308

1744

2180

<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:

0.306

Hom.:

27739

Bravo

AF:

0.292

TwinsUK

AF:

0.338

AC:

1254

ALSPAC

AF:

0.336

AC:

1295

ESP6500AA

AF:

0.202

AC:

792

ESP6500EA

AF:

0.311

AC:

2584

ExAC

AF:

0.285

AC:

34448

Asia WGS

AF:

0.156

AC:

544

AN:

3478

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 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

- -

Clinical Genetics, Academic 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

0.048

BayesDel_addAF

Benign

-0.83

BayesDel_noAF

Benign

-0.82

CADD

Benign

8.0

(source)

DANN

Benign

0.79

DEOGEN2

Benign

0.0036

.;.;T;.;T;.

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.0039

LIST_S2

Benign

0.046

T;T;T;.;.;T

MetaRNN

Benign

0.00024

T;T;T;T;T;T

MetaSVM

Benign

-0.91

MutationAssessor

Benign

0.0

N;N;N;N;N;.

PhyloP100

-0.16

PrimateAI

Benign

0.30

PROVEAN

Benign

1.1

N;N;N;N;N;N

REVEL

Benign

0.032

Sift

Benign

0.14

T;T;T;T;T;T

Sift4G

Benign

0.56

T;T;T;T;T;T

Polyphen

0.0020

B;.;B;.;B;.

Vest4

0.033

MPC

0.076

ClinPred

0.0057

GERP RS

-0.56

Varity_R

0.046

gMVP

0.20

Mutation Taster

=100/0

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