5-73923129-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The ENST00000437974.5(ARHGEF28):c.4991C>T(p.Pro1664Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.199 in 1,534,866 control chromosomes in the GnomAD database, including 36,510 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. P1664P) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.28 ( 7666 hom., cov: 32)

Exomes 𝑓: 0.19 ( 28844 hom. )

Consequence

ARHGEF28
ENST00000437974.5 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: -1.00

Publications

20 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 (MetaRNN=4.4029228E-5).

BP6

Variant 5-73923129-C-T is Benign according to our data. Variant chr5-73923129-C-T is described in ClinVar as Benign. ClinVar VariationId is 257375.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.5 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
ARHGEF28	NM_001177693.2 link	c.4948+11554C>T		intron_variant	Intron 35 of 35	ENST00000513042.7	NP_001171164.1
ARHGEF28	NM_001080479.3 link	c.4991C>T	p.Pro1664Leu	missense_variant	Exon 36 of 37		NP_001073948.2
ARHGEF28	NM_001388076.1 link	c.4654+11554C>T		intron_variant	Intron 34 of 34		NP_001375005.1
ARHGEF28	NM_001244364.2 link	c.4009+11554C>T		intron_variant	Intron 27 of 27		NP_001231293.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ARHGEF28	ENST00000513042.7 link	c.4948+11554C>T		intron_variant	Intron 35 of 35	5	NM_001177693.2	ENSP00000441436.1

Frequencies

GnomAD3 genomes

AF:

0.278

AC:

42216

AN:

151816

Hom.:

7641

Cov.:

show subpopulations

Gnomad AFR

AF:

0.506

Gnomad AMI

AF:

0.146

Gnomad AMR

AF:

0.323

Gnomad ASJ

AF:

0.134

Gnomad EAS

AF:

0.125

Gnomad SAS

AF:

0.329

Gnomad FIN

AF:

0.162

Gnomad MID

AF:

0.146

Gnomad NFE

AF:

0.167

Gnomad OTH

AF:

0.225

GnomAD2 exomes

AF:

0.246

AC:

33596

AN:

136596

AF XY:

0.239

show subpopulations

Gnomad AFR exome

AF:

0.525

Gnomad AMR exome

AF:

0.408

Gnomad ASJ exome

AF:

0.140

Gnomad EAS exome

AF:

0.118

Gnomad FIN exome

AF:

0.159

Gnomad NFE exome

AF:

0.169

Gnomad OTH exome

AF:

0.197

GnomAD4 exome

AF:

0.190

AC:

263266

AN:

1382932

Hom.:

28844

Cov.:

AF XY:

0.193

AC XY:

131438

AN XY:

682408

show subpopulations

African (AFR)

AF:

0.512

AC:

16152

AN:

31546

American (AMR)

AF:

0.393

AC:

13962

AN:

35570

Ashkenazi Jewish (ASJ)

AF:

0.136

AC:

3424

AN:

25158

East Asian (EAS)

AF:

0.151

AC:

5409

AN:

35718

South Asian (SAS)

AF:

0.313

AC:

24751

AN:

79100

European-Finnish (FIN)

AF:

0.161

AC:

5455

AN:

33868

Middle Eastern (MID)

AF:

0.152

AC:

865

AN:

5692

European-Non Finnish (NFE)

AF:

0.169

AC:

182080

AN:

1078400

Other (OTH)

AF:

0.193

AC:

11168

AN:

57880

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.457

Heterozygous variant carriers

10336

20672

31007

41343

51679

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

6814

13628

20442

27256

34070

<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:

0.278

AC:

42306

AN:

151934

Hom.:

7666

Cov.:

AF XY:

0.276

AC XY:

20498

AN XY:

74264

show subpopulations

African (AFR)

AF:

0.506

AC:

20955

AN:

41394

American (AMR)

AF:

0.323

AC:

4924

AN:

15250

Ashkenazi Jewish (ASJ)

AF:

0.134

AC:

464

AN:

3470

East Asian (EAS)

AF:

0.125

AC:

647

AN:

5164

South Asian (SAS)

AF:

0.329

AC:

1582

AN:

4812

European-Finnish (FIN)

AF:

0.162

AC:

1706

AN:

10556

Middle Eastern (MID)

AF:

0.146

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.167

AC:

11364

AN:

67978

Other (OTH)

AF:

0.232

AC:

488

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1370

2740

4109

5479

6849

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

404

808

1212

1616

2020

<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:

0.200

Hom.:

18152

Bravo

AF:

0.299

TwinsUK

AF:

0.166

AC:

614

ALSPAC

AF:

0.165

AC:

634

ExAC

AF:

0.232

AC:

4005

Asia WGS

AF:

0.259

AC:

900

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

Clinical Genetics, Academic 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

- -

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

- -

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

AlphaMissense

Benign

0.074

BayesDel_addAF

Benign

-0.85

BayesDel_noAF

Benign

-0.85

CADD

Benign

0.37

(source)

DANN

Benign

0.42

DEOGEN2

Benign

0.0067

.;.;T

Eigen

Benign

-1.9

Eigen_PC

Benign

-1.9

FATHMM_MKL

Benign

0.0059

LIST_S2

Benign

0.48

T;.;T

MetaRNN

Benign

0.000044

T;T;T

MetaSVM

Benign

-0.91

PhyloP100

-1.0

PrimateAI

Benign

0.17

PROVEAN

Benign

-0.46

N;N;N

REVEL

Benign

0.0070

Sift

Benign

1.0

T;T;T

Sift4G

Uncertain

0.053

T;T;D

Polyphen

0.0

.;.;B

Vest4

0.058

MPC

0.071

ClinPred

0.00072

GERP RS

-6.6

gMVP

0.072

Mutation Taster

=98/2

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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