rs2931423

Variant names:

Variant summary

Our verdict is Benign. The variant received -15 ACMG points: 1P and 16B. PP3BP6_Very_StrongBA1

The NM_001177693.2(ARHGEF28):c.2283C>T(p.Gly761Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.312 in 1,613,324 control chromosomes in the GnomAD database, including 81,160 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.29 ( 6591 hom., cov: 32)

Exomes 𝑓: 0.31 ( 74569 hom. )

Consequence

ARHGEF28
NM_001177693.2 synonymous

Scores

Clinical Significance

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

Conservation

PhyloP100: -0.464

Publications

18 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 -15 ACMG points.

PP3

Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

BP6

Variant 5-73868006-C-T is Benign according to our data. Variant chr5-73868006-C-T is described in ClinVar as Benign. ClinVar VariationId is 257362.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.378 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ARHGEF28	NM_001177693.2 link	c.2283C>T	p.Gly761Gly	synonymous_variant	Exon 19 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.2283C>T	p.Gly761Gly	synonymous_variant	Exon 19 of 36	5	NM_001177693.2	ENSP00000441436.1		Q8N1W1-1

Frequencies

GnomAD3 genomes

AF:

0.285

AC:

43370

AN:

151924

Hom.:

6582

Cov.:

show subpopulations

Gnomad AFR

AF:

0.210

Gnomad AMI

AF:

0.320

Gnomad AMR

AF:

0.386

Gnomad ASJ

AF:

0.304

Gnomad EAS

AF:

0.139

Gnomad SAS

AF:

0.195

Gnomad FIN

AF:

0.294

Gnomad MID

AF:

0.301

Gnomad NFE

AF:

0.324

Gnomad OTH

AF:

0.285

GnomAD2 exomes

AF:

0.301

AC:

74801

AN:

248468

AF XY:

0.292

show subpopulations

Gnomad AFR exome

AF:

0.209

Gnomad AMR exome

AF:

0.463

Gnomad ASJ exome

AF:

0.299

Gnomad EAS exome

AF:

0.138

Gnomad FIN exome

AF:

0.300

Gnomad NFE exome

AF:

0.318

Gnomad OTH exome

AF:

0.296

GnomAD4 exome

AF:

0.315

AC:

459673

AN:

1461282

Hom.:

74569

Cov.:

AF XY:

0.310

AC XY:

225364

AN XY:

726948

show subpopulations

African (AFR)

AF:

0.204

AC:

6826

AN:

33476

American (AMR)

AF:

0.451

AC:

20145

AN:

44672

Ashkenazi Jewish (ASJ)

AF:

0.295

AC:

7706

AN:

26130

East Asian (EAS)

AF:

0.116

AC:

4600

AN:

39694

South Asian (SAS)

AF:

0.201

AC:

17332

AN:

86240

European-Finnish (FIN)

AF:

0.299

AC:

15949

AN:

53376

Middle Eastern (MID)

AF:

0.266

AC:

1537

AN:

5768

European-Non Finnish (NFE)

AF:

0.331

AC:

367512

AN:

1111564

Other (OTH)

AF:

0.299

AC:

18066

AN:

60362

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.464

Heterozygous variant carriers

17829

35657

53486

71314

89143

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

11940

23880

35820

47760

59700

<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:

0.285

AC:

43408

AN:

152042

Hom.:

6591

Cov.:

AF XY:

0.281

AC XY:

20850

AN XY:

74310

show subpopulations

African (AFR)

AF:

0.210

AC:

8714

AN:

41476

American (AMR)

AF:

0.387

AC:

5907

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.304

AC:

1053

AN:

3468

East Asian (EAS)

AF:

0.139

AC:

716

AN:

5160

South Asian (SAS)

AF:

0.196

AC:

942

AN:

4814

European-Finnish (FIN)

AF:

0.294

AC:

3105

AN:

10570

Middle Eastern (MID)

AF:

0.306

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.324

AC:

21997

AN:

67960

Other (OTH)

AF:

0.281

AC:

593

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1576

3153

4729

6306

7882

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

434

868

1302

1736

2170

<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:

0.310

Hom.:

30964

Bravo

AF:

0.292

Asia WGS

AF:

0.156

AC:

544

AN:

3476

EpiCase

AF:

0.315

EpiControl

AF:

0.312

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance:Benign

Review Status:no assertion criteria provided

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

- -

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: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 v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.66

CADD

Benign

(source)

DANN

Benign

0.65

PhyloP100

-0.46

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.52

Details are displayed if max score is > 0.2

DS_DG_spliceai

0.52

Position offset: -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