5-73909872-C-G

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.4622C>G(p.Ala1541Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0378 in 1,520,832 control chromosomes in the GnomAD database, including 1,227 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. A1541A) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.040 ( 124 hom., cov: 31)

Exomes 𝑓: 0.038 ( 1103 hom. )

Consequence

ARHGEF28
NM_001177693.2 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.353

Publications

4 publications found

Variant links:

COSMIC-nc: COSV104383008

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=0.0027357042).

BP6

Variant 5-73909872-C-G is Benign according to our data. Variant chr5-73909872-C-G is described in ClinVar as Benign. ClinVar VariationId is 257372.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0546 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ARHGEF28	NM_001177693.2 link	c.4622C>G	p.Ala1541Gly	missense_variant	Exon 34 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.4622C>G	p.Ala1541Gly	missense_variant	Exon 34 of 36	5	NM_001177693.2	ENSP00000441436.1

Frequencies

GnomAD3 genomes

AF:

0.0396

AC:

6020

AN:

152066

Hom.:

124

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0443

Gnomad AMI

AF:

0.00879

Gnomad AMR

AF:

0.0329

Gnomad ASJ

AF:

0.0138

Gnomad EAS

AF:

0.000194

Gnomad SAS

AF:

0.0608

Gnomad FIN

AF:

0.0626

Gnomad MID

AF:

0.0190

Gnomad NFE

AF:

0.0381

Gnomad OTH

AF:

0.0349

GnomAD2 exomes

AF:

0.0341

AC:

4985

AN:

146130

AF XY:

0.0360

show subpopulations

Gnomad AFR exome

AF:

0.0429

Gnomad AMR exome

AF:

0.0236

Gnomad ASJ exome

AF:

0.00930

Gnomad EAS exome

AF:

0.0000689

Gnomad FIN exome

AF:

0.0549

Gnomad NFE exome

AF:

0.0361

Gnomad OTH exome

AF:

0.0426

GnomAD4 exome

AF:

0.0376

AC:

51508

AN:

1368648

Hom.:

1103

Cov.:

AF XY:

0.0384

AC XY:

25891

AN XY:

674736

show subpopulations

African (AFR)

AF:

0.0462

AC:

1410

AN:

30500

American (AMR)

AF:

0.0250

AC:

769

AN:

30802

Ashkenazi Jewish (ASJ)

AF:

0.00985

AC:

206

AN:

20910

East Asian (EAS)

AF:

0.000103

AC:

AN:

38938

South Asian (SAS)

AF:

0.0589

AC:

4236

AN:

71966

European-Finnish (FIN)

AF:

0.0566

AC:

1973

AN:

34840

Middle Eastern (MID)

AF:

0.0373

AC:

155

AN:

4154

European-Non Finnish (NFE)

AF:

0.0377

AC:

40746

AN:

1080044

Other (OTH)

AF:

0.0356

AC:

2009

AN:

56494

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.457

Heterozygous variant carriers

2853

5706

8559

11412

14265

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:

0.0396

AC:

6022

AN:

152184

Hom.:

124

Cov.:

AF XY:

0.0421

AC XY:

3129

AN XY:

74404

show subpopulations

African (AFR)

AF:

0.0443

AC:

1840

AN:

41524

American (AMR)

AF:

0.0328

AC:

502

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.0138

AC:

AN:

3472

East Asian (EAS)

AF:

0.000195

AC:

AN:

5140

South Asian (SAS)

AF:

0.0603

AC:

291

AN:

4828

European-Finnish (FIN)

AF:

0.0626

AC:

664

AN:

10608

Middle Eastern (MID)

AF:

0.0204

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0381

AC:

2589

AN:

67998

Other (OTH)

AF:

0.0346

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

Heterozygous variant carriers

294

587

881

1174

1468

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

148

222

296

370

<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:

0.0205

Hom.:

Bravo

AF:

0.0373

TwinsUK

AF:

0.0340

AC:

126

ALSPAC

AF:

0.0306

AC:

118

ESP6500AA

AF:

0.0277

AC:

ESP6500EA

AF:

0.0244

AC:

182

ExAC

AF:

0.0327

AC:

3791

Asia WGS

AF:

0.0300

AC:

106

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Genome Diagnostics Laboratory, Amsterdam University 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: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

- -

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

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.58

BayesDel_noAF

Benign

-0.56

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.0038

.;.;T;.;T;.;T

Eigen

Benign

-0.86

Eigen_PC

Benign

-0.90

FATHMM_MKL

Benign

0.30

LIST_S2

Uncertain

0.87

D;D;D;.;.;D;D

MetaRNN

Benign

0.0027

T;T;T;T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.1

L;L;L;L;L;.;.

PhyloP100

0.35

PrimateAI

Benign

0.36

PROVEAN

Benign

-0.26

N;N;N;N;N;N;N

REVEL

Benign

0.036

Sift

Benign

0.094

T;T;T;T;T;T;T

Sift4G

Benign

0.26

T;T;T;T;T;T;T

Polyphen

0.16

B;.;B;.;B;.;D

Vest4

0.19

MPC

0.26

ClinPred

0.0064

GERP RS

3.4

Varity_R

0.025

gMVP

0.21

Mutation Taster

=95/5

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