Genetic Variant ARHGEF28:p.Ser560Ser (chr5-73849020-A-G) – ACMG Classification: Benign (-21 pts)

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_001177693.2(ARHGEF28):c.1680A>G(p.Ser560Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.593 in 1,575,968 control chromosomes in the GnomAD database, including 282,631 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.67 ( 35574 hom., cov: 32)

Exomes 𝑓: 0.59 ( 247057 hom. )

Consequence

ARHGEF28
NM_001177693.2 synonymous

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.175

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 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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.47).

BP6

Variant 5-73849020-A-G is Benign according to our data. Variant chr5-73849020-A-G is described in ClinVar as Benign. ClinVar VariationId is 257359.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=0.175 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.891 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.1680A>G	p.Ser560Ser	synonymous	Exon 13 of 36	NP_001171164.1
ARHGEF28	NM_001080479.3		c.1680A>G	p.Ser560Ser	synonymous	Exon 13 of 37	NP_001073948.2
ARHGEF28	NM_001388078.1		c.1680A>G	p.Ser560Ser	synonymous	Exon 13 of 35	NP_001375007.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
ARHGEF28	ENST00000513042.7	TSL:5 MANE Select	c.1680A>G	p.Ser560Ser	synonymous	Exon 13 of 36	ENSP00000441436.1
ARHGEF28	ENST00000437974.5	TSL:1	c.1680A>G	p.Ser560Ser	synonymous	Exon 12 of 36	ENSP00000411459.1
ARHGEF28	ENST00000426542.6	TSL:1	c.1680A>G	p.Ser560Ser	synonymous	Exon 12 of 35	ENSP00000412175.2

Frequencies

GnomAD3 genomes

AF:

0.667

AC:

101220

AN:

151854

Hom.:

35507

Cov.:

show subpopulations

Gnomad AFR

AF:

0.899

Gnomad AMI

AF:

0.726

Gnomad AMR

AF:

0.642

Gnomad ASJ

AF:

0.578

Gnomad EAS

AF:

0.522

Gnomad SAS

AF:

0.623

Gnomad FIN

AF:

0.522

Gnomad MID

AF:

0.598

Gnomad NFE

AF:

0.571

Gnomad OTH

AF:

0.655

GnomAD2 exomes

AF:

0.596

AC:

119906

AN:

201102

AF XY:

0.591

show subpopulations

Gnomad AFR exome

AF:

0.904

Gnomad AMR exome

AF:

0.639

Gnomad ASJ exome

AF:

0.584

Gnomad EAS exome

AF:

0.523

Gnomad FIN exome

AF:

0.524

Gnomad NFE exome

AF:

0.563

Gnomad OTH exome

AF:

0.587

GnomAD4 exome

AF:

0.585

AC:

833504

AN:

1423994

Hom.:

247057

Cov.:

AF XY:

0.584

AC XY:

411654

AN XY:

704906

show subpopulations

African (AFR)

AF:

0.916

AC:

30026

AN:

32794

American (AMR)

AF:

0.637

AC:

25417

AN:

39872

Ashkenazi Jewish (ASJ)

AF:

0.576

AC:

14721

AN:

25556

East Asian (EAS)

AF:

0.478

AC:

18441

AN:

38548

South Asian (SAS)

AF:

0.613

AC:

49818

AN:

81226

European-Finnish (FIN)

AF:

0.533

AC:

27304

AN:

51270

Middle Eastern (MID)

AF:

0.643

AC:

3680

AN:

5724

European-Non Finnish (NFE)

AF:

0.577

AC:

628775

AN:

1090016

Other (OTH)

AF:

0.599

AC:

35322

AN:

58988

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.459

Heterozygous variant carriers

16222

32443

48665

64886

81108

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

17712

35424

53136

70848

88560

<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:

0.667

AC:

101348

AN:

151974

Hom.:

35574

Cov.:

AF XY:

0.662

AC XY:

49124

AN XY:

74250

show subpopulations

African (AFR)

AF:

0.899

AC:

37320

AN:

41520

American (AMR)

AF:

0.643

AC:

9812

AN:

15268

Ashkenazi Jewish (ASJ)

AF:

0.578

AC:

2003

AN:

3468

East Asian (EAS)

AF:

0.522

AC:

2694

AN:

5162

South Asian (SAS)

AF:

0.624

AC:

2997

AN:

4804

European-Finnish (FIN)

AF:

0.522

AC:

5509

AN:

10544

Middle Eastern (MID)

AF:

0.609

AC:

179

AN:

294

European-Non Finnish (NFE)

AF:

0.571

AC:

38785

AN:

67892

Other (OTH)

AF:

0.657

AC:

1387

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

1570

3139

4709

6278

7848

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

788

1576

2364

3152

3940

<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:

0.608

Hom.:

48312

Bravo

AF:

0.689

Asia WGS

AF:

0.622

AC:

2159

AN:

3476

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

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

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

not provided

Benign:2

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

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.47

CADD

Benign

7.1

(source)

DANN

Benign

0.64

PhyloP100

0.17

Mutation Taster

=100/0

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

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

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over