5-73846471-C-T

Variant names:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001177693.2(ARHGEF28):c.1631C>T(p.Ser544Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.268 in 1,611,306 control chromosomes in the GnomAD database, including 60,119 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt.

Frequency

Genomes: 𝑓 0.24 ( 4596 hom., cov: 31)

Exomes 𝑓: 0.27 ( 55523 hom. )

Consequence

ARHGEF28
NM_001177693.2 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.0500

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.004041642).

BP6

Variant 5-73846471-C-T is Benign according to our data. Variant chr5-73846471-C-T is described in ClinVar as [Benign]. Clinvar id is 257358.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-73846471-C-T is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.281 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ARHGEF28	NM_001177693.2 link	c.1631C>T	p.Ser544Leu	missense_variant	Exon 12 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.1631C>T	p.Ser544Leu	missense_variant	Exon 12 of 36	5	NM_001177693.2	ENSP00000441436.1		Q8N1W1-1

Frequencies

GnomAD3 genomes

AF:

0.236

AC:

35844

AN:

151854

Hom.:

4595

Cov.:

show subpopulations

Gnomad AFR

AF:

0.157

Gnomad AMI

AF:

0.368

Gnomad AMR

AF:

0.280

Gnomad ASJ

AF:

0.276

Gnomad EAS

AF:

0.0710

Gnomad SAS

AF:

0.188

Gnomad FIN

AF:

0.253

Gnomad MID

AF:

0.253

Gnomad NFE

AF:

0.284

Gnomad OTH

AF:

0.230

GnomAD3 exomes

AF:

0.245

AC:

61011

AN:

248670

Hom.:

8015

AF XY:

0.243

AC XY:

32721

AN XY:

134892

show subpopulations

Gnomad AFR exome

AF:

0.156

Gnomad AMR exome

AF:

0.310

Gnomad ASJ exome

AF:

0.278

Gnomad EAS exome

AF:

0.0638

Gnomad SAS exome

AF:

0.189

Gnomad FIN exome

AF:

0.262

Gnomad NFE exome

AF:

0.276

Gnomad OTH exome

AF:

0.251

GnomAD4 exome

AF:

0.271

AC:

395870

AN:

1459334

Hom.:

55523

Cov.:

AF XY:

0.269

AC XY:

194991

AN XY:

726074

show subpopulations

Gnomad4 AFR exome

AF:

0.151

Gnomad4 AMR exome

AF:

0.302

Gnomad4 ASJ exome

AF:

0.274

Gnomad4 EAS exome

AF:

0.0584

Gnomad4 SAS exome

AF:

0.190

Gnomad4 FIN exome

AF:

0.259

Gnomad4 NFE exome

AF:

0.289

Gnomad4 OTH exome

AF:

0.256

GnomAD4 genome

AF:

0.236

AC:

35855

AN:

151972

Hom.:

4596

Cov.:

AF XY:

0.232

AC XY:

17197

AN XY:

74272

show subpopulations

Gnomad4 AFR

AF:

0.157

Gnomad4 AMR

AF:

0.280

Gnomad4 ASJ

AF:

0.276

Gnomad4 EAS

AF:

0.0714

Gnomad4 SAS

AF:

0.189

Gnomad4 FIN

AF:

0.253

Gnomad4 NFE

AF:

0.284

Gnomad4 OTH

AF:

0.227

Alfa

AF:

0.266

Hom.:

11821

Bravo

AF:

0.236

TwinsUK

AF:

0.295

AC:

1095

ALSPAC

AF:

0.292

AC:

1124

ESP6500AA

AF:

0.160

AC:

586

ESP6500EA

AF:

0.273

AC:

2232

ExAC

AF:

0.240

AC:

28977

Asia WGS

AF:

0.120

AC:

419

AN:

3478

EpiCase

AF:

0.272

EpiControl

AF:

0.272

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 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

- -

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

- -

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

0.063

BayesDel_addAF

Benign

-0.82

BayesDel_noAF

Benign

-0.80

CADD

Benign

9.2

DANN

Benign

0.95

DEOGEN2

Benign

0.0060

.;.;T;.;T;.

Eigen

Benign

-1.1

Eigen_PC

Benign

-0.99

FATHMM_MKL

Benign

0.020

LIST_S2

Benign

0.71

T;T;T;.;.;T

MetaRNN

Benign

0.0040

T;T;T;T;T;T

MetaSVM

Benign

-0.90

MutationAssessor

Benign

-0.12

N;N;N;N;N;.

PrimateAI

Benign

0.29

PROVEAN

Benign

-0.78

N;N;N;N;N;N

REVEL

Benign

0.031

Sift

Benign

0.17

T;T;T;T;T;T

Sift4G

Benign

0.64

T;T;T;T;T;T

Polyphen

0.0010

B;.;B;.;B;.

Vest4

0.040

MPC

0.063

ClinPred

0.0072

GERP RS

-0.95

Varity_R

0.026

gMVP

0.20

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.070

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over