rs2973571

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.1631C>T(p.Ser544Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.268 in 1,611,306 control chromosomes in the GnomAD database, including 60,119 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 0.24 ( 4596 hom., cov: 31)

Exomes 𝑓: 0.27 ( 55523 hom. )

Consequence

ARHGEF28
NM_001177693.2 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.0500

Publications

24 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, SD Classification: MODERATE, LIMITED Submitted by: Genomics England PanelApp, ClinGen

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=0.004041642).

BP6

Variant 5-73846471-C-T is Benign according to our data. Variant chr5-73846471-C-T is described in ClinVar as Benign. ClinVar VariationId is 257358.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.281 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	UniProt
ARHGEF28	NM_001177693.2	MANE Select	c.1631C>T	p.Ser544Leu	missense	Exon 12 of 36	NP_001171164.1	Q8N1W1-1
ARHGEF28	NM_001080479.3		c.1631C>T	p.Ser544Leu	missense	Exon 12 of 37	NP_001073948.2	Q8N1W1-6
ARHGEF28	NM_001388078.1		c.1631C>T	p.Ser544Leu	missense	Exon 12 of 35	NP_001375007.1	Q8N1W1-4

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ARHGEF28	ENST00000513042.7	TSL:5 MANE Select	c.1631C>T	p.Ser544Leu	missense	Exon 12 of 36	ENSP00000441436.1	Q8N1W1-1
ARHGEF28	ENST00000437974.5	TSL:1	c.1631C>T	p.Ser544Leu	missense	Exon 11 of 36	ENSP00000411459.1	Q8N1W1-6
ARHGEF28	ENST00000426542.6	TSL:1	c.1631C>T	p.Ser544Leu	missense	Exon 11 of 35	ENSP00000412175.2	Q8N1W1-1

Frequencies

GnomAD3 genomes

AF:

0.236

AC:

35844

AN:

151854

Hom.:

4595

Cov.:

show subpopulations

Gnomad AFR

AF:

0.157

Gnomad AMI

AF:

0.368

Gnomad AMR

AF:

0.280

Gnomad ASJ

AF:

0.276

Gnomad EAS

AF:

0.0710

Gnomad SAS

AF:

0.188

Gnomad FIN

AF:

0.253

Gnomad MID

AF:

0.253

Gnomad NFE

AF:

0.284

Gnomad OTH

AF:

0.230

GnomAD2 exomes

AF:

0.245

AC:

61011

AN:

248670

AF XY:

0.243

show subpopulations

Gnomad AFR exome

AF:

0.156

Gnomad AMR exome

AF:

0.310

Gnomad ASJ exome

AF:

0.278

Gnomad EAS exome

AF:

0.0638

Gnomad FIN exome

AF:

0.262

Gnomad NFE exome

AF:

0.276

Gnomad OTH exome

AF:

0.251

GnomAD4 exome

AF:

0.271

AC:

395870

AN:

1459334

Hom.:

55523

Cov.:

AF XY:

0.269

AC XY:

194991

AN XY:

726074

show subpopulations

African (AFR)

AF:

0.151

AC:

5045

AN:

33420

American (AMR)

AF:

0.302

AC:

13507

AN:

44702

Ashkenazi Jewish (ASJ)

AF:

0.274

AC:

7157

AN:

26114

East Asian (EAS)

AF:

0.0584

AC:

2315

AN:

39670

South Asian (SAS)

AF:

0.190

AC:

16413

AN:

86162

European-Finnish (FIN)

AF:

0.259

AC:

13846

AN:

53370

Middle Eastern (MID)

AF:

0.245

AC:

1409

AN:

5752

European-Non Finnish (NFE)

AF:

0.289

AC:

320729

AN:

1109840

Other (OTH)

AF:

0.256

AC:

15449

AN:

60304

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.465

Heterozygous variant carriers

13010

26019

39029

52038

65048

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

10622

21244

31866

42488

53110

<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:

0.236

AC:

35855

AN:

151972

Hom.:

4596

Cov.:

AF XY:

0.232

AC XY:

17197

AN XY:

74272

show subpopulations

African (AFR)

AF:

0.157

AC:

6502

AN:

41456

American (AMR)

AF:

0.280

AC:

4271

AN:

15256

Ashkenazi Jewish (ASJ)

AF:

0.276

AC:

956

AN:

3466

East Asian (EAS)

AF:

0.0714

AC:

369

AN:

5170

South Asian (SAS)

AF:

0.189

AC:

911

AN:

4814

European-Finnish (FIN)

AF:

0.253

AC:

2662

AN:

10538

Middle Eastern (MID)

AF:

0.252

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.284

AC:

19295

AN:

67954

Other (OTH)

AF:

0.227

AC:

480

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

1374

2748

4121

5495

6869

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

376

752

1128

1504

1880

<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:

0.261

Hom.:

22122

Bravo

AF:

0.236

TwinsUK

AF:

0.295

AC:

1095

ALSPAC

AF:

0.292

AC:

1124

ESP6500AA

AF:

0.160

AC:

586

ESP6500EA

AF:

0.273

AC:

2232

ExAC

AF:

0.240

AC:

28977

Asia WGS

AF:

0.120

AC:

419

AN:

3478

EpiCase

AF:

0.272

EpiControl

AF:

0.272

ClinVar

ClinVar submissions

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

0.063

BayesDel_addAF

Benign

-0.82

BayesDel_noAF

Benign

-0.80

CADD

Benign

9.2

(source)

DANN

Benign

0.95

DEOGEN2

Benign

0.0060

Eigen

Benign

-1.1

Eigen_PC

Benign

-0.99

FATHMM_MKL

Benign

0.020

LIST_S2

Benign

0.71

MetaRNN

Benign

0.0040

MetaSVM

Benign

-0.90

MutationAssessor

Benign

-0.12

PhyloP100

0.050

PrimateAI

Benign

0.29

PROVEAN

Benign

-0.78

REVEL

Benign

0.031

Sift

Benign

0.17

Sift4G

Benign

0.64

Polyphen

0.0010

Vest4

0.040

MPC

0.063

ClinPred

0.0072

GERP RS

-0.95

Varity_R

0.026

gMVP

0.20

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.070

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over