rs1478453

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

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

The NM_001177693.2(ARHGEF28):c.4920T>A(p.His1640Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.371 in 1,607,754 control chromosomes in the GnomAD database, including 114,467 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 0.37 ( 10389 hom., cov: 32)

Exomes 𝑓: 0.37 ( 104078 hom. )

Consequence

ARHGEF28
NM_001177693.2 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: -0.484

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=2.567172E-4).

BP6

Variant 5-73911547-T-A is Benign according to our data. Variant chr5-73911547-T-A is described in ClinVar as [Benign]. Clinvar id is 257374.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-73911547-T-A is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.395 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ARHGEF28	NM_001177693.2 link	c.4920T>A	p.His1640Gln	missense_variant	Exon 35 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.4920T>A	p.His1640Gln	missense_variant	Exon 35 of 36	5	NM_001177693.2	ENSP00000441436.1		Q8N1W1-1

Frequencies

GnomAD3 genomes

AF:

0.365

AC:

55546

AN:

151978

Hom.:

10373

Cov.:

show subpopulations

Gnomad AFR

AF:

0.377

Gnomad AMI

AF:

0.388

Gnomad AMR

AF:

0.274

Gnomad ASJ

AF:

0.474

Gnomad EAS

AF:

0.226

Gnomad SAS

AF:

0.206

Gnomad FIN

AF:

0.343

Gnomad MID

AF:

0.329

Gnomad NFE

AF:

0.399

Gnomad OTH

AF:

0.343

GnomAD3 exomes

AF:

0.330

AC:

79122

AN:

240052

Hom.:

14045

AF XY:

0.331

AC XY:

42960

AN XY:

129850

show subpopulations

Gnomad AFR exome

AF:

0.370

Gnomad AMR exome

AF:

0.190

Gnomad ASJ exome

AF:

0.480

Gnomad EAS exome

AF:

0.230

Gnomad SAS exome

AF:

0.211

Gnomad FIN exome

AF:

0.342

Gnomad NFE exome

AF:

0.399

Gnomad OTH exome

AF:

0.350

GnomAD4 exome

AF:

0.372

AC:

541640

AN:

1455656

Hom.:

104078

Cov.:

AF XY:

0.368

AC XY:

266181

AN XY:

723240

show subpopulations

Gnomad4 AFR exome

AF:

0.372

Gnomad4 AMR exome

AF:

0.200

Gnomad4 ASJ exome

AF:

0.481

Gnomad4 EAS exome

AF:

0.206

Gnomad4 SAS exome

AF:

0.207

Gnomad4 FIN exome

AF:

0.343

Gnomad4 NFE exome

AF:

0.397

Gnomad4 OTH exome

AF:

0.370

GnomAD4 genome

AF:

0.365

AC:

55590

AN:

152098

Hom.:

10389

Cov.:

AF XY:

0.358

AC XY:

26620

AN XY:

74356

show subpopulations

Gnomad4 AFR

AF:

0.377

Gnomad4 AMR

AF:

0.274

Gnomad4 ASJ

AF:

0.474

Gnomad4 EAS

AF:

0.225

Gnomad4 SAS

AF:

0.206

Gnomad4 FIN

AF:

0.343

Gnomad4 NFE

AF:

0.399

Gnomad4 OTH

AF:

0.346

Alfa

AF:

0.394

Hom.:

9232

Bravo

AF:

0.363

TwinsUK

AF:

0.398

AC:

1476

ALSPAC

AF:

0.397

AC:

1531

ESP6500AA

AF:

0.359

AC:

1490

ESP6500EA

AF:

0.398

AC:

3351

ExAC

AF:

0.331

AC:

40010

Asia WGS

AF:

0.242

AC:

843

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

- -

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

- -

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

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jun 09, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.080

BayesDel_addAF

Benign

-0.79

BayesDel_noAF

Benign

-0.77

CADD

Benign

0.10

DANN

Benign

0.48

DEOGEN2

Benign

0.0027

.;.;T;.;T;.;T

Eigen

Benign

-1.8

Eigen_PC

Benign

-1.7

FATHMM_MKL

Benign

0.030

LIST_S2

Benign

0.56

T;T;T;.;.;T;T

MetaRNN

Benign

0.00026

T;T;T;T;T;T;T

MetaSVM

Benign

-0.93

MutationAssessor

Benign

1.1

L;L;L;L;L;.;.

PrimateAI

Benign

0.28

PROVEAN

Benign

0.49

N;N;N;N;N;N;N

REVEL

Benign

0.021

Sift

Benign

0.58

T;T;T;T;T;T;T

Sift4G

Benign

0.47

T;T;T;T;T;T;T

Polyphen

0.0030

B;.;B;.;B;.;B

Vest4

0.12

MutPred

0.045

Gain of phosphorylation at S1642 (P = 0.2469);Gain of phosphorylation at S1642 (P = 0.2469);Gain of phosphorylation at S1642 (P = 0.2469);Gain of phosphorylation at S1642 (P = 0.2469);Gain of phosphorylation at S1642 (P = 0.2469);.;.;

MPC

0.071

ClinPred

0.0012

GERP RS

-1.8

Varity_R

0.027

gMVP

0.13

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

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