NM_001177693.2:c.4642C>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.4642C>T(p.Pro1548Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0373 in 1,506,738 control chromosomes in the GnomAD database, including 1,179 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.037 ( 107 hom., cov: 31)

Exomes 𝑓: 0.037 ( 1072 hom. )

Consequence

ARHGEF28
NM_001177693.2 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: -1.07

Publications

6 publications found

Variant links:

COSMIC-nc: COSV104383009

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, SD Classification: MODERATE, LIMITED Submitted by: Genomics England PanelApp, ClinGen

ARHGEF28 links:

ENSG00000304540 (HGNC:):

ENSG00000304540 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=0.0023434758).

BP6

Variant 5-73909892-C-T is Benign according to our data. Variant chr5-73909892-C-T is described in ClinVar as Benign. ClinVar VariationId is 257373.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0547 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001177693.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ARHGEF28	NM_001177693.2	MANE Select	c.4642C>T	p.Pro1548Ser	missense	Exon 34 of 36	NP_001171164.1	Q8N1W1-1
ARHGEF28	NM_001080479.3		c.4642C>T	p.Pro1548Ser	missense	Exon 34 of 37	NP_001073948.2	Q8N1W1-6
ARHGEF28	NM_001388078.1		c.4642C>T	p.Pro1548Ser	missense	Exon 34 of 35	NP_001375007.1	Q8N1W1-4

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ARHGEF28	ENST00000513042.7	TSL:5 MANE Select	c.4642C>T	p.Pro1548Ser	missense	Exon 34 of 36	ENSP00000441436.1	Q8N1W1-1
ARHGEF28	ENST00000437974.5	TSL:1	c.4642C>T	p.Pro1548Ser	missense	Exon 33 of 36	ENSP00000411459.1	Q8N1W1-6
ARHGEF28	ENST00000426542.6	TSL:1	c.4642C>T	p.Pro1548Ser	missense	Exon 33 of 35	ENSP00000412175.2	Q8N1W1-1

Frequencies

GnomAD3 genomes

AF:

0.0371

AC:

5644

AN:

152058

Hom.:

107

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0362

Gnomad AMI

AF:

0.00877

Gnomad AMR

AF:

0.0306

Gnomad ASJ

AF:

0.0138

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.0608

Gnomad FIN

AF:

0.0625

Gnomad MID

AF:

0.0191

Gnomad NFE

AF:

0.0381

Gnomad OTH

AF:

0.0344

GnomAD2 exomes

AF:

0.0333

AC:

4715

AN:

141702

AF XY:

0.0352

show subpopulations

Gnomad AFR exome

AF:

0.0342

Gnomad AMR exome

AF:

0.0229

Gnomad ASJ exome

AF:

0.00980

Gnomad EAS exome

AF:

0.000137

Gnomad FIN exome

AF:

0.0532

Gnomad NFE exome

AF:

0.0365

Gnomad OTH exome

AF:

0.0407

GnomAD4 exome

AF:

0.0374

AC:

50613

AN:

1354562

Hom.:

1072

Cov.:

AF XY:

0.0381

AC XY:

25356

AN XY:

665428

show subpopulations

African (AFR)

AF:

0.0368

AC:

1106

AN:

30066

American (AMR)

AF:

0.0244

AC:

721

AN:

29512

Ashkenazi Jewish (ASJ)

AF:

0.0100

AC:

202

AN:

20170

East Asian (EAS)

AF:

0.000103

AC:

AN:

38768

South Asian (SAS)

AF:

0.0591

AC:

4140

AN:

70102

European-Finnish (FIN)

AF:

0.0566

AC:

1932

AN:

34122

Middle Eastern (MID)

AF:

0.0379

AC:

151

AN:

3988

European-Non Finnish (NFE)

AF:

0.0377

AC:

40388

AN:

1071832

Other (OTH)

AF:

0.0352

AC:

1969

AN:

56002

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.457

Heterozygous variant carriers

2828

5655

8483

11310

14138

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1562

3124

4686

6248

7810

<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:

0.0371

AC:

5646

AN:

152176

Hom.:

107

Cov.:

AF XY:

0.0396

AC XY:

2948

AN XY:

74412

show subpopulations

African (AFR)

AF:

0.0361

AC:

1501

AN:

41522

American (AMR)

AF:

0.0306

AC:

468

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.0138

AC:

AN:

3470

East Asian (EAS)

AF:

0.000194

AC:

AN:

5156

South Asian (SAS)

AF:

0.0604

AC:

291

AN:

4818

European-Finnish (FIN)

AF:

0.0625

AC:

663

AN:

10610

Middle Eastern (MID)

AF:

0.0205

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.0381

AC:

2588

AN:

67980

Other (OTH)

AF:

0.0341

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.491

Heterozygous variant carriers

279

559

838

1118

1397

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

140

210

280

350

<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:

0.0370

Hom.:

330

Bravo

AF:

0.0343

TwinsUK

AF:

0.0340

AC:

126

ALSPAC

AF:

0.0304

AC:

117

ESP6500AA

AF:

0.0276

AC:

ESP6500EA

AF:

0.0265

AC:

195

ExAC

AF:

0.0325

AC:

3738

Asia WGS

AF:

0.0300

AC:

105

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (4)

not provided (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.077

BayesDel_addAF

Benign

-0.69

BayesDel_noAF

Benign

-0.72

CADD

Benign

0.0050

(source)

DANN

Benign

0.47

DEOGEN2

Benign

0.0034

Eigen

Benign

-1.4

Eigen_PC

Benign

-1.4

FATHMM_MKL

Benign

0.042

LIST_S2

Benign

0.26

MetaRNN

Benign

0.0023

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.2

PhyloP100

-1.1

PrimateAI

Benign

0.23

PROVEAN

Benign

0.24

REVEL

Benign

0.010

Sift

Benign

0.84

Sift4G

Benign

0.72

Polyphen

0.0030

Vest4

0.067

MPC

0.071

ClinPred

0.000019

GERP RS

-4.5

Varity_R

0.014

gMVP

0.094

Mutation Taster

=99/1

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over