Variant 5-73901264-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2

The NM_001177693.2(ARHGEF28):c.4054G>A(p.Val1352Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00392 in 1,612,966 control chromosomes in the GnomAD database, including 13 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0031 ( 1 hom., cov: 32)

Exomes 𝑓: 0.0040 ( 12 hom. )

Consequence

ARHGEF28
NM_001177693.2 missense

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 2.26

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 -16 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0044407547).

BP6

Variant 5-73901264-G-A is Benign according to our data. Variant chr5-73901264-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 257370.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-73901264-G-A is described in Lovd as [Likely_benign].

BS2

High Homozygotes in GnomAdExome4 at 12 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ARHGEF28	NM_001177693.2 linkuse as main transcript	c.4054G>A	p.Val1352Ile	missense_variant	31/36	ENST00000513042.7	NP_001171164.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ARHGEF28	ENST00000513042.7 linkuse as main transcript	c.4054G>A	p.Val1352Ile	missense_variant	31/36	5	NM_001177693.2	ENSP00000441436		Q8N1W1-1

Frequencies

GnomAD3 genomes

AF:

0.00314

AC:

478

AN:

152070

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000894

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00439

Gnomad ASJ

AF:

0.00519

Gnomad EAS

AF:

0.000771

Gnomad SAS

AF:

0.00228

Gnomad FIN

AF:

0.00302

Gnomad MID

AF:

0.0127

Gnomad NFE

AF:

0.00435

Gnomad OTH

AF:

0.00431

GnomAD3 exomes

AF:

0.00293

AC:

728

AN:

248556

Hom.:

AF XY:

0.00298

AC XY:

402

AN XY:

134762

show subpopulations

Gnomad AFR exome

AF:

0.000843

Gnomad AMR exome

AF:

0.00163

Gnomad ASJ exome

AF:

0.00399

Gnomad EAS exome

AF:

0.000278

Gnomad SAS exome

AF:

0.00139

Gnomad FIN exome

AF:

0.00190

Gnomad NFE exome

AF:

0.00454

Gnomad OTH exome

AF:

0.00314

GnomAD4 exome

AF:

0.00400

AC:

5848

AN:

1460778

Hom.:

Cov.:

AF XY:

0.00399

AC XY:

2900

AN XY:

726628

show subpopulations

Gnomad4 AFR exome

AF:

0.000687

Gnomad4 AMR exome

AF:

0.00141

Gnomad4 ASJ exome

AF:

0.00556

Gnomad4 EAS exome

AF:

0.000403

Gnomad4 SAS exome

AF:

0.00187

Gnomad4 FIN exome

AF:

0.00251

Gnomad4 NFE exome

AF:

0.00455

Gnomad4 OTH exome

AF:

0.00393

GnomAD4 genome

AF:

0.00314

AC:

478

AN:

152188

Hom.:

Cov.:

AF XY:

0.00332

AC XY:

247

AN XY:

74402

show subpopulations

Gnomad4 AFR

AF:

0.000892

Gnomad4 AMR

AF:

0.00438

Gnomad4 ASJ

AF:

0.00519

Gnomad4 EAS

AF:

0.000773

Gnomad4 SAS

AF:

0.00229

Gnomad4 FIN

AF:

0.00302

Gnomad4 NFE

AF:

0.00435

Gnomad4 OTH

AF:

0.00427

Alfa

AF:

0.00393

Hom.:

Bravo

AF:

0.00284

TwinsUK

AF:

0.00512

AC:

ALSPAC

AF:

0.00441

AC:

ESP6500AA

AF:

0.00126

AC:

ESP6500EA

AF:

0.00494

AC:

ExAC

AF:

0.00304

AC:

367

Asia WGS

AF:

0.000866

AC:

AN:

3478

EpiCase

AF:

0.00469

EpiControl

AF:

0.00380

ClinVar

Significance: Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 31, 2019	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2023	ARHGEF28: BP4 -

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.089

BayesDel_addAF

Benign

-0.61

BayesDel_noAF

Benign

-0.64

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.0091

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

Eigen

Benign

0.044

Eigen_PC

Benign

0.12

FATHMM_MKL

Benign

0.65

LIST_S2

Benign

0.66

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

M_CAP

Benign

0.0063

MetaRNN

Benign

0.0044

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

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.1

M;M;M;M;M;.;.

MutationTaster

Benign

1.0

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

PrimateAI

Benign

0.29

PROVEAN

Benign

-0.15

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

REVEL

Benign

0.070

Sift

Benign

0.19

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

Sift4G

Benign

0.26

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

Polyphen

0.23

B;.;P;.;P;.;P

Vest4

0.11

MVP

0.20

MPC

0.063

ClinPred

0.0068

GERP RS

3.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.056

gMVP

0.058

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

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