rs146562116

Variant names:

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BA1

The NM_001177693.2(ARHGEF28):c.3753C>T(p.Asp1251Asp) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0201 in 1,613,868 control chromosomes in the GnomAD database, including 1,218 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.020 ( 114 hom., cov: 33)

Exomes 𝑓: 0.020 ( 1104 hom. )

Consequence

ARHGEF28
NM_001177693.2 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: -0.231

Publications

6 publications found

Variant links:

COSMIC-nc: COSV104382974

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 -19 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.39).

BP6

Variant 5-73894487-C-T is Benign according to our data. Variant chr5-73894487-C-T is described in ClinVar as Benign. ClinVar VariationId is 257369.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.231 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0925 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ARHGEF28	NM_001177693.2 link	c.3753C>T	p.Asp1251Asp	synonymous_variant	Exon 29 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.3753C>T	p.Asp1251Asp	synonymous_variant	Exon 29 of 36	5	NM_001177693.2	ENSP00000441436.1		Q8N1W1-1

Frequencies

GnomAD3 genomes

AF:

0.0198

AC:

3018

AN:

152148

Hom.:

112

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00657

Gnomad AMI

AF:

0.00110

Gnomad AMR

AF:

0.0961

Gnomad ASJ

AF:

0.0196

Gnomad EAS

AF:

0.00212

Gnomad SAS

AF:

0.0238

Gnomad FIN

AF:

0.00471

Gnomad MID

AF:

0.0348

Gnomad NFE

AF:

0.0143

Gnomad OTH

AF:

0.0229

GnomAD2 exomes

AF:

0.0384

AC:

9554

AN:

248892

AF XY:

0.0326

show subpopulations

Gnomad AFR exome

AF:

0.00615

Gnomad AMR exome

AF:

0.192

Gnomad ASJ exome

AF:

0.0179

Gnomad EAS exome

AF:

0.00245

Gnomad FIN exome

AF:

0.00538

Gnomad NFE exome

AF:

0.0134

Gnomad OTH exome

AF:

0.0288

GnomAD4 exome

AF:

0.0202

AC:

29485

AN:

1461602

Hom.:

1104

Cov.:

AF XY:

0.0195

AC XY:

14147

AN XY:

727074

show subpopulations

African (AFR)

AF:

0.00454

AC:

152

AN:

33476

American (AMR)

AF:

0.179

AC:

7983

AN:

44676

Ashkenazi Jewish (ASJ)

AF:

0.0194

AC:

507

AN:

26132

East Asian (EAS)

AF:

0.00116

AC:

AN:

39700

South Asian (SAS)

AF:

0.0282

AC:

2430

AN:

86236

European-Finnish (FIN)

AF:

0.00581

AC:

310

AN:

53398

Middle Eastern (MID)

AF:

0.0140

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0151

AC:

16768

AN:

1111842

Other (OTH)

AF:

0.0200

AC:

1208

AN:

60374

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.469

Heterozygous variant carriers

1302

2603

3905

5206

6508

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

752

1504

2256

3008

3760

<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:

0.0199

AC:

3029

AN:

152266

Hom.:

114

Cov.:

AF XY:

0.0201

AC XY:

1498

AN XY:

74454

show subpopulations

African (AFR)

AF:

0.00657

AC:

273

AN:

41550

American (AMR)

AF:

0.0966

AC:

1478

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.0196

AC:

AN:

3470

East Asian (EAS)

AF:

0.00212

AC:

AN:

5180

South Asian (SAS)

AF:

0.0239

AC:

115

AN:

4820

European-Finnish (FIN)

AF:

0.00471

AC:

AN:

10608

Middle Eastern (MID)

AF:

0.0374

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0143

AC:

974

AN:

68022

Other (OTH)

AF:

0.0227

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

147

294

440

587

734

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

102

136

170

<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:

0.0155

Hom.:

Bravo

AF:

0.0283

Asia WGS

AF:

0.0190

AC:

AN:

3478

EpiCase

AF:

0.0141

EpiControl

AF:

0.0141

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

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

- -

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not specified

Benign:2

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

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

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.39

CADD

Benign

6.9

(source)

DANN

Benign

0.36

PhyloP100

-0.23

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Mutation Taster

=98/2

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over