NM_001177693.2:c.3018C>T

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.3018C>T(p.Tyr1006Tyr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.127 in 1,569,962 control chromosomes in the GnomAD database, including 13,827 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.14 ( 1560 hom., cov: 32)

Exomes 𝑓: 0.13 ( 12267 hom. )

Consequence

ARHGEF28
NM_001177693.2 synonymous

Scores

Clinical Significance

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

Conservation

PhyloP100: 1.25

Publications

15 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 -19 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.34).

BP6

Variant 5-73883847-C-T is Benign according to our data. Variant chr5-73883847-C-T is described in ClinVar as Benign. ClinVar VariationId is 257366.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=1.25 with no splicing effect.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.275 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ARHGEF28	NM_001177693.2 link	c.3018C>T	p.Tyr1006Tyr	synonymous_variant	Exon 24 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.3018C>T	p.Tyr1006Tyr	synonymous_variant	Exon 24 of 36	5	NM_001177693.2	ENSP00000441436.1		Q8N1W1-1

Frequencies

GnomAD3 genomes

AF:

0.136

AC:

20591

AN:

151828

Hom.:

1560

Cov.:

show subpopulations

Gnomad AFR

AF:

0.170

Gnomad AMI

AF:

0.268

Gnomad AMR

AF:

0.0896

Gnomad ASJ

AF:

0.102

Gnomad EAS

AF:

0.287

Gnomad SAS

AF:

0.182

Gnomad FIN

AF:

0.105

Gnomad MID

AF:

0.190

Gnomad NFE

AF:

0.115

Gnomad OTH

AF:

0.131

GnomAD2 exomes

AF:

0.128

AC:

24278

AN:

189534

AF XY:

0.130

show subpopulations

Gnomad AFR exome

AF:

0.158

Gnomad AMR exome

AF:

0.0787

Gnomad ASJ exome

AF:

0.111

Gnomad EAS exome

AF:

0.276

Gnomad FIN exome

AF:

0.103

Gnomad NFE exome

AF:

0.113

Gnomad OTH exome

AF:

0.121

GnomAD4 exome

AF:

0.126

AC:

178372

AN:

1418016

Hom.:

12267

Cov.:

AF XY:

0.126

AC XY:

88612

AN XY:

701144

show subpopulations

African (AFR)

AF:

0.168

AC:

5434

AN:

32266

American (AMR)

AF:

0.0793

AC:

3094

AN:

39002

Ashkenazi Jewish (ASJ)

AF:

0.106

AC:

2667

AN:

25278

East Asian (EAS)

AF:

0.284

AC:

10700

AN:

37634

South Asian (SAS)

AF:

0.169

AC:

13254

AN:

78638

European-Finnish (FIN)

AF:

0.110

AC:

5605

AN:

51172

Middle Eastern (MID)

AF:

0.172

AC:

978

AN:

5700

European-Non Finnish (NFE)

AF:

0.118

AC:

129086

AN:

1089554

Other (OTH)

AF:

0.129

AC:

7554

AN:

58772

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.465

Heterozygous variant carriers

6770

13540

20309

27079

33849

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

4982

9964

14946

19928

24910

<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:

0.136

AC:

20602

AN:

151946

Hom.:

1560

Cov.:

AF XY:

0.136

AC XY:

10080

AN XY:

74250

show subpopulations

African (AFR)

AF:

0.170

AC:

7030

AN:

41458

American (AMR)

AF:

0.0893

AC:

1364

AN:

15270

Ashkenazi Jewish (ASJ)

AF:

0.102

AC:

355

AN:

3470

East Asian (EAS)

AF:

0.288

AC:

1482

AN:

5154

South Asian (SAS)

AF:

0.181

AC:

869

AN:

4806

European-Finnish (FIN)

AF:

0.105

AC:

1102

AN:

10538

Middle Eastern (MID)

AF:

0.197

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.115

AC:

7811

AN:

67940

Other (OTH)

AF:

0.136

AC:

287

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

885

1770

2655

3540

4425

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

232

464

696

928

1160

<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:

0.124

Hom.:

4849

Bravo

AF:

0.137

Asia WGS

AF:

0.214

AC:

743

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

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 DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus 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 v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.34

CADD

Benign

7.9

(source)

DANN

Benign

0.92

PhyloP100

1.2

Mutation Taster

=90/10

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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