chr5-73752994-G-A

Variant names:

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BS1BS2

The NM_001177693.2(ARHGEF28):c.267G>A(p.Val89Val) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0115 in 1,613,496 control chromosomes in the GnomAD database, including 177 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0088 ( 13 hom., cov: 32)

Exomes 𝑓: 0.012 ( 164 hom. )

Consequence

ARHGEF28
NM_001177693.2 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 1.16

Publications

4 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=-0.42).

BP6

Variant 5-73752994-G-A is Benign according to our data. Variant chr5-73752994-G-A is described in ClinVar as Benign. ClinVar VariationId is 257365.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=1.15 with no splicing effect.

BS1

Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00877 (1336/152334) while in subpopulation SAS AF = 0.0195 (94/4822). AF 95% confidence interval is 0.0163. There are 13 homozygotes in GnomAd4. There are 643 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 13 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ARHGEF28	NM_001177693.2 link	c.267G>A	p.Val89Val	synonymous_variant	Exon 4 of 36	ENST00000513042.7	NP_001171164.1	Q8N1W1-1
ARHGEF28	NM_001080479.3 link	c.267G>A	p.Val89Val	synonymous_variant	Exon 4 of 37		NP_001073948.2	Q8N1W1-6
ARHGEF28	NM_001388078.1 link	c.267G>A	p.Val89Val	synonymous_variant	Exon 4 of 35		NP_001375007.1
ARHGEF28	NM_001388076.1 link	c.181+3010G>A		intron_variant	Intron 3 of 34		NP_001375005.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ARHGEF28	ENST00000513042.7 link	c.267G>A	p.Val89Val	synonymous_variant	Exon 4 of 36	5	NM_001177693.2	ENSP00000441436.1		Q8N1W1-1

Frequencies

GnomAD3 genomes

AF:

0.00876

AC:

1334

AN:

152216

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00164

Gnomad AMI

AF:

0.113

Gnomad AMR

AF:

0.00530

Gnomad ASJ

AF:

0.0351

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.0193

Gnomad FIN

AF:

0.00151

Gnomad MID

AF:

0.0158

Gnomad NFE

AF:

0.0121

Gnomad OTH

AF:

0.0100

GnomAD2 exomes

AF:

0.0108

AC:

2665

AN:

247902

AF XY:

0.0118

show subpopulations

Gnomad AFR exome

AF:

0.00176

Gnomad AMR exome

AF:

0.00460

Gnomad ASJ exome

AF:

0.0334

Gnomad EAS exome

AF:

0.000111

Gnomad FIN exome

AF:

0.00172

Gnomad NFE exome

AF:

0.0122

Gnomad OTH exome

AF:

0.0129

GnomAD4 exome

AF:

0.0118

AC:

17245

AN:

1461162

Hom.:

164

Cov.:

AF XY:

0.0123

AC XY:

8953

AN XY:

726782

show subpopulations

African (AFR)

AF:

0.00146

AC:

AN:

33474

American (AMR)

AF:

0.00466

AC:

208

AN:

44640

Ashkenazi Jewish (ASJ)

AF:

0.0352

AC:

921

AN:

26130

East Asian (EAS)

AF:

0.0000756

AC:

AN:

39692

South Asian (SAS)

AF:

0.0199

AC:

1709

AN:

86048

European-Finnish (FIN)

AF:

0.00176

AC:

AN:

53390

Middle Eastern (MID)

AF:

0.0236

AC:

136

AN:

5768

European-Non Finnish (NFE)

AF:

0.0120

AC:

13304

AN:

1111656

Other (OTH)

AF:

0.0136

AC:

821

AN:

60364

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.489

Heterozygous variant carriers

1011

2021

3032

4042

5053

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

516

1032

1548

2064

2580

<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:

0.00877

AC:

1336

AN:

152334

Hom.:

Cov.:

AF XY:

0.00863

AC XY:

643

AN XY:

74486

show subpopulations

African (AFR)

AF:

0.00164

AC:

AN:

41586

American (AMR)

AF:

0.00529

AC:

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.0351

AC:

122

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5184

South Asian (SAS)

AF:

0.0195

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.00151

AC:

AN:

10628

Middle Eastern (MID)

AF:

0.0204

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0121

AC:

825

AN:

68018

Other (OTH)

AF:

0.00992

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

140

211

281

351

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.0126

Hom.:

Bravo

AF:

0.00900

Asia WGS

AF:

0.00549

AC:

AN:

3478

EpiCase

AF:

0.0142

EpiControl

AF:

0.0127

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

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

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance:Likely benign

Review Status:no assertion criteria provided

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

-0.42

CADD

Benign

(source)

DANN

Benign

0.74

PhyloP100

1.2

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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