5-73909638-G-A

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.4388G>A(p.Arg1463Gln) variant causes a missense change. The variant allele was found at a frequency of 0.0377 in 1,548,766 control chromosomes in the GnomAD database, including 1,234 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1463W) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.036 ( 115 hom., cov: 32)

Exomes 𝑓: 0.038 ( 1119 hom. )

Consequence

ARHGEF28
NM_001177693.2 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 4.94

Publications

7 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:

ENSG00000304540 (HGNC:):

ENSG00000304540 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=0.001647383).

BP6

Variant 5-73909638-G-A is Benign according to our data. Variant chr5-73909638-G-A is described in ClinVar as Benign. ClinVar VariationId is 257371.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0534 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001177693.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
ARHGEF28	NM_001177693.2	MANE Select	c.4388G>A	p.Arg1463Gln	missense	Exon 34 of 36	NP_001171164.1
ARHGEF28	NM_001080479.3		c.4388G>A	p.Arg1463Gln	missense	Exon 34 of 37	NP_001073948.2
ARHGEF28	NM_001388078.1		c.4388G>A	p.Arg1463Gln	missense	Exon 34 of 35	NP_001375007.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
ARHGEF28	ENST00000513042.7	TSL:5 MANE Select	c.4388G>A	p.Arg1463Gln	missense	Exon 34 of 36	ENSP00000441436.1
ARHGEF28	ENST00000437974.5	TSL:1	c.4388G>A	p.Arg1463Gln	missense	Exon 33 of 36	ENSP00000411459.1
ARHGEF28	ENST00000426542.6	TSL:1	c.4388G>A	p.Arg1463Gln	missense	Exon 33 of 35	ENSP00000412175.2

Frequencies

GnomAD3 genomes

AF:

0.0360

AC:

5482

AN:

152174

Hom.:

114

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0346

Gnomad AMI

AF:

0.00877

Gnomad AMR

AF:

0.0249

Gnomad ASJ

AF:

0.0150

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.0592

Gnomad FIN

AF:

0.0629

Gnomad MID

AF:

0.0190

Gnomad NFE

AF:

0.0379

Gnomad OTH

AF:

0.0321

GnomAD2 exomes

AF:

0.0374

AC:

5374

AN:

143664

AF XY:

0.0386

show subpopulations

Gnomad AFR exome

AF:

0.0310

Gnomad AMR exome

AF:

0.0216

Gnomad ASJ exome

AF:

0.0124

Gnomad EAS exome

AF:

0.0000937

Gnomad FIN exome

AF:

0.0638

Gnomad NFE exome

AF:

0.0408

Gnomad OTH exome

AF:

0.0406

GnomAD4 exome

AF:

0.0379

AC:

52881

AN:

1396474

Hom.:

1119

Cov.:

AF XY:

0.0386

AC XY:

26550

AN XY:

688544

show subpopulations

African (AFR)

AF:

0.0369

AC:

1167

AN:

31604

American (AMR)

AF:

0.0232

AC:

829

AN:

35694

Ashkenazi Jewish (ASJ)

AF:

0.0116

AC:

293

AN:

25164

East Asian (EAS)

AF:

0.0000839

AC:

AN:

35740

South Asian (SAS)

AF:

0.0566

AC:

4486

AN:

79244

European-Finnish (FIN)

AF:

0.0604

AC:

2872

AN:

47570

Middle Eastern (MID)

AF:

0.0354

AC:

187

AN:

5278

European-Non Finnish (NFE)

AF:

0.0381

AC:

41065

AN:

1078308

Other (OTH)

AF:

0.0342

AC:

1979

AN:

57872

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.482

Heterozygous variant carriers

3547

7094

10640

14187

17734

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1568

3136

4704

6272

7840

<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:

0.0361

AC:

5494

AN:

152292

Hom.:

115

Cov.:

AF XY:

0.0384

AC XY:

2863

AN XY:

74466

show subpopulations

African (AFR)

AF:

0.0348

AC:

1446

AN:

41570

American (AMR)

AF:

0.0249

AC:

381

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.0150

AC:

AN:

3468

East Asian (EAS)

AF:

0.000193

AC:

AN:

5176

South Asian (SAS)

AF:

0.0591

AC:

285

AN:

4824

European-Finnish (FIN)

AF:

0.0629

AC:

668

AN:

10616

Middle Eastern (MID)

AF:

0.0204

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0379

AC:

2580

AN:

68018

Other (OTH)

AF:

0.0318

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

270

539

809

1078

1348

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

136

204

272

340

<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:

0.0343

Hom.:

Bravo

AF:

0.0330

TwinsUK

AF:

0.0340

AC:

126

ALSPAC

AF:

0.0311

AC:

120

ESP6500AA

AF:

0.0266

AC:

103

ESP6500EA

AF:

0.0251

AC:

199

ExAC

AF:

0.0207

AC:

2000

Asia WGS

AF:

0.0290

AC:

102

AN:

3478

ClinVar

ClinVar submissions as Germline

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (4)

not provided (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.071

BayesDel_addAF

Benign

-0.60

BayesDel_noAF

Benign

-0.59

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.0042

Eigen

Benign

0.073

Eigen_PC

Benign

0.22

FATHMM_MKL

Uncertain

0.97

LIST_S2

Benign

0.82

MetaRNN

Benign

0.0016

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.4

PhyloP100

4.9

PrimateAI

Benign

0.32

PROVEAN

Benign

-0.43

REVEL

Benign

0.056

Sift

Benign

0.35

Sift4G

Benign

0.43

Polyphen

0.33

Vest4

0.12

MPC

0.094

ClinPred

0.0076

GERP RS

5.2

Varity_R

0.092

gMVP

0.060

Mutation Taster

=97/3

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over