rs6453022

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.851C>A(p.Pro284Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.513 in 1,553,786 control chromosomes in the GnomAD database, including 206,069 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 0.56 ( 23978 hom., cov: 30)

Exomes 𝑓: 0.51 ( 182091 hom. )

Consequence

ARHGEF28
NM_001177693.2 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 1.90

Publications

36 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:

ENSG00000249293 (HGNC:):

ENSG00000249293 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=1.4842926E-6).

BP6

Variant 5-73780686-C-A is Benign according to our data. Variant chr5-73780686-C-A is described in ClinVar as Benign. ClinVar VariationId is 257378.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.683 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
ARHGEF28	NM_001177693.2 link	c.851C>A	p.Pro284Gln	missense_variant	Exon 7 of 36	ENST00000513042.7	NP_001171164.1
ARHGEF28	NM_001080479.3 link	c.851C>A	p.Pro284Gln	missense_variant	Exon 7 of 37		NP_001073948.2
ARHGEF28	NM_001388078.1 link	c.851C>A	p.Pro284Gln	missense_variant	Exon 7 of 35		NP_001375007.1
ARHGEF28	NM_001388076.1 link	c.557C>A	p.Pro186Gln	missense_variant	Exon 6 of 35		NP_001375005.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ARHGEF28	ENST00000513042.7 link	c.851C>A	p.Pro284Gln	missense_variant	Exon 7 of 36	5	NM_001177693.2	ENSP00000441436.1

Frequencies

GnomAD3 genomes

AF:

0.556

AC:

84189

AN:

151482

Hom.:

23930

Cov.:

show subpopulations

Gnomad AFR

AF:

0.690

Gnomad AMI

AF:

0.614

Gnomad AMR

AF:

0.556

Gnomad ASJ

AF:

0.485

Gnomad EAS

AF:

0.498

Gnomad SAS

AF:

0.542

Gnomad FIN

AF:

0.486

Gnomad MID

AF:

0.472

Gnomad NFE

AF:

0.494

Gnomad OTH

AF:

0.538

GnomAD2 exomes

AF:

0.525

AC:

86213

AN:

164138

AF XY:

0.521

show subpopulations

Gnomad AFR exome

AF:

0.685

Gnomad AMR exome

AF:

0.588

Gnomad ASJ exome

AF:

0.499

Gnomad EAS exome

AF:

0.505

Gnomad FIN exome

AF:

0.488

Gnomad NFE exome

AF:

0.495

Gnomad OTH exome

AF:

0.512

GnomAD4 exome

AF:

0.508

AC:

712262

AN:

1402184

Hom.:

182091

Cov.:

AF XY:

0.507

AC XY:

351054

AN XY:

692062

show subpopulations

African (AFR)

AF:

0.696

AC:

22098

AN:

31738

American (AMR)

AF:

0.580

AC:

20955

AN:

36140

Ashkenazi Jewish (ASJ)

AF:

0.490

AC:

12354

AN:

25206

East Asian (EAS)

AF:

0.457

AC:

16509

AN:

36124

South Asian (SAS)

AF:

0.533

AC:

42278

AN:

79390

European-Finnish (FIN)

AF:

0.491

AC:

24203

AN:

49326

Middle Eastern (MID)

AF:

0.512

AC:

2914

AN:

5694

European-Non Finnish (NFE)

AF:

0.500

AC:

540656

AN:

1080392

Other (OTH)

AF:

0.521

AC:

30295

AN:

58174

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.457

Heterozygous variant carriers

17672

35344

53017

70689

88361

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

16114

32228

48342

64456

80570

<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:

0.556

AC:

84289

AN:

151602

Hom.:

23978

Cov.:

AF XY:

0.556

AC XY:

41153

AN XY:

74026

show subpopulations

African (AFR)

AF:

0.690

AC:

28492

AN:

41294

American (AMR)

AF:

0.556

AC:

8468

AN:

15228

Ashkenazi Jewish (ASJ)

AF:

0.485

AC:

1680

AN:

3464

East Asian (EAS)

AF:

0.496

AC:

2553

AN:

5142

South Asian (SAS)

AF:

0.542

AC:

2593

AN:

4788

European-Finnish (FIN)

AF:

0.486

AC:

5083

AN:

10460

Middle Eastern (MID)

AF:

0.466

AC:

137

AN:

294

European-Non Finnish (NFE)

AF:

0.494

AC:

33581

AN:

67914

Other (OTH)

AF:

0.542

AC:

1142

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.508

Heterozygous variant carriers

1834

3669

5503

7338

9172

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

722

1444

2166

2888

3610

<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:

0.512

Hom.:

87058

Bravo

AF:

0.569

TwinsUK

AF:

0.510

AC:

1890

ALSPAC

AF:

0.506

AC:

1949

ESP6500AA

AF:

0.703

AC:

2702

ESP6500EA

AF:

0.507

AC:

4177

ExAC

AF:

0.414

AC:

43300

Asia WGS

AF:

0.544

AC:

1893

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

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Clinical Genetics, Academic 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

- -

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Jun 09, 2021

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.062

BayesDel_addAF

Benign

-0.75

BayesDel_noAF

Benign

-0.71

CADD

Benign

(source)

DANN

Benign

0.70

DEOGEN2

Benign

0.0028

.;.;T;.;T

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.013

LIST_S2

Benign

0.15

T;T;T;.;.

MetaRNN

Benign

0.0000015

T;T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-1.8

N;N;N;N;N

PhyloP100

1.9

PrimateAI

Benign

0.29

PROVEAN

Benign

-0.030

N;N;N;N;N

REVEL

Benign

0.050

Sift

Benign

0.89

T;T;T;T;T

Sift4G

Benign

0.47

T;T;T;T;T

Polyphen

0.0

B;.;B;.;B

Vest4

0.048

MPC

0.065

ClinPred

0.0020

GERP RS

-0.022

Varity_R

0.052

gMVP

0.16

Mutation Taster

=85/15

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

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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