chr5-73795324-C-T

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.964-7C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0854 in 1,612,788 control chromosomes in the GnomAD database, including 14,150 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.19 ( 5359 hom., cov: 32)

Exomes 𝑓: 0.075 ( 8791 hom. )

Consequence

ARHGEF28
NM_001177693.2 splice_region, intron

Scores

Splicing: ADA: 0.00003687

Clinical Significance

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

Conservation

PhyloP100: -0.691

Publications

6 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 -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.9).

BP6

Variant 5-73795324-C-T is Benign according to our data. Variant chr5-73795324-C-T is described in ClinVar as Benign. ClinVar VariationId is 257380.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.474 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein
ARHGEF28	NM_001177693.2 link	c.964-7C>T	splice_region_variant, intron_variant	Intron 8 of 35	ENST00000513042.7	NP_001171164.1
ARHGEF28	NM_001080479.3 link	c.964-7C>T	splice_region_variant, intron_variant	Intron 8 of 36		NP_001073948.2
ARHGEF28	NM_001388078.1 link	c.964-7C>T	splice_region_variant, intron_variant	Intron 8 of 34		NP_001375007.1
ARHGEF28	NM_001388076.1 link	c.670-7C>T	splice_region_variant, intron_variant	Intron 7 of 34		NP_001375005.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ARHGEF28	ENST00000513042.7 link	c.964-7C>T		splice_region_variant, intron_variant	Intron 8 of 35	5	NM_001177693.2	ENSP00000441436.1

Frequencies

GnomAD3 genomes

AF:

0.189

AC:

28698

AN:

151998

Hom.:

5343

Cov.:

show subpopulations

Gnomad AFR

AF:

0.479

Gnomad AMI

AF:

0.0769

Gnomad AMR

AF:

0.153

Gnomad ASJ

AF:

0.0441

Gnomad EAS

AF:

0.240

Gnomad SAS

AF:

0.167

Gnomad FIN

AF:

0.0563

Gnomad MID

AF:

0.0981

Gnomad NFE

AF:

0.0490

Gnomad OTH

AF:

0.159

GnomAD2 exomes

AF:

0.122

AC:

30264

AN:

248858

AF XY:

0.113

show subpopulations

Gnomad AFR exome

AF:

0.491

Gnomad AMR exome

AF:

0.166

Gnomad ASJ exome

AF:

0.0382

Gnomad EAS exome

AF:

0.255

Gnomad FIN exome

AF:

0.0573

Gnomad NFE exome

AF:

0.0478

Gnomad OTH exome

AF:

0.0894

GnomAD4 exome

AF:

0.0746

AC:

109025

AN:

1460672

Hom.:

8791

Cov.:

AF XY:

0.0753

AC XY:

54730

AN XY:

726672

show subpopulations

African (AFR)

AF:

0.490

AC:

16352

AN:

33386

American (AMR)

AF:

0.164

AC:

7321

AN:

44648

Ashkenazi Jewish (ASJ)

AF:

0.0400

AC:

1045

AN:

26124

East Asian (EAS)

AF:

0.222

AC:

8816

AN:

39670

South Asian (SAS)

AF:

0.159

AC:

13675

AN:

86140

European-Finnish (FIN)

AF:

0.0552

AC:

2944

AN:

53376

Middle Eastern (MID)

AF:

0.0909

AC:

524

AN:

5766

European-Non Finnish (NFE)

AF:

0.0471

AC:

52392

AN:

1111220

Other (OTH)

AF:

0.0987

AC:

5956

AN:

60342

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.480

Heterozygous variant carriers

4387

8773

13160

17546

21933

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

2378

4756

7134

9512

11890

<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:

0.189

AC:

28765

AN:

152116

Hom.:

5359

Cov.:

AF XY:

0.189

AC XY:

14062

AN XY:

74392

show subpopulations

African (AFR)

AF:

0.479

AC:

19854

AN:

41440

American (AMR)

AF:

0.153

AC:

2340

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.0441

AC:

153

AN:

3470

East Asian (EAS)

AF:

0.240

AC:

1243

AN:

5176

South Asian (SAS)

AF:

0.168

AC:

808

AN:

4820

European-Finnish (FIN)

AF:

0.0563

AC:

596

AN:

10588

Middle Eastern (MID)

AF:

0.105

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0490

AC:

3335

AN:

68014

Other (OTH)

AF:

0.159

AC:

335

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

906

1812

2718

3624

4530

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

264

528

792

1056

1320

<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:

0.110

Hom.:

1149

Bravo

AF:

0.210

Asia WGS

AF:

0.258

AC:

896

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

- -

Clinical Genetics, Academic 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

- -

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

-0.90

CADD

Benign

0.30

(source)

DANN

Benign

0.35

PhyloP100

-0.69

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000037

dbscSNV1_RF

Benign

0.0

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