5-73749936-A-G

Position:

chr5-73749936-A-G

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM2BP4_StrongBP6_Moderate

The NM_001177693.2(ARHGEF28):c.133A>G(p.Met45Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000185 in 1,613,924 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 Likely benign (★).

Frequency

Genomes: 𝑓 0.00021 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00018 ( 0 hom. )

Consequence

ARHGEF28
NM_001177693.2 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:2

Conservation

PhyloP100: 0.361

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 Likely_benign. Variant got -4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.010992199).

BP6

Variant 5-73749936-A-G is Benign according to our data. Variant chr5-73749936-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 2511392.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
ARHGEF28	NM_001177693.2 linkuse as main transcript	c.133A>G	p.Met45Val	missense_variant	3/36	ENST00000513042.7	NP_001171164.1
ARHGEF28	NM_001080479.3 linkuse as main transcript	c.133A>G	p.Met45Val	missense_variant	3/37		NP_001073948.2
ARHGEF28	NM_001388078.1 linkuse as main transcript	c.133A>G	p.Met45Val	missense_variant	3/35		NP_001375007.1
ARHGEF28	NM_001388076.1 linkuse as main transcript	c.133A>G	p.Met45Val	missense_variant	3/35		NP_001375005.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ARHGEF28	ENST00000513042.7 linkuse as main transcript	c.133A>G	p.Met45Val	missense_variant	3/36	5	NM_001177693.2	ENSP00000441436		Q8N1W1-1

Frequencies

GnomAD3 genomes

AF:

0.000210

AC:

AN:

152232

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000942

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000456

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000257

AC:

AN:

249238

Hom.:

AF XY:

0.000222

AC XY:

AN XY:

135202

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000928

Gnomad NFE exome

AF:

0.000540

Gnomad OTH exome

AF:

0.000165

GnomAD4 exome

AF:

0.000182

AC:

266

AN:

1461692

Hom.:

Cov.:

AF XY:

0.000188

AC XY:

137

AN XY:

727132

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.0000383

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.000112

Gnomad4 NFE exome

AF:

0.000223

Gnomad4 OTH exome

AF:

0.000182

GnomAD4 genome

AF:

0.000210

AC:

AN:

152232

Hom.:

Cov.:

AF XY:

0.000134

AC XY:

AN XY:

74368

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.0000942

Gnomad4 NFE

AF:

0.000456

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000377

Hom.:

Bravo

AF:

0.000140

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000472

AC:

ExAC

AF:

0.000330

AC:

EpiCase

AF:

0.000382

EpiControl

AF:

0.000178

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 07, 2023

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

ARHGEF28-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 07, 2022

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.062

BayesDel_addAF

Benign

-0.60

BayesDel_noAF

Benign

-0.67

CADD

Benign

0.60

DANN

Benign

0.36

DEOGEN2

Benign

0.0041

.;.;T;.;.;T

Eigen

Benign

-1.8

Eigen_PC

Benign

-1.7

FATHMM_MKL

Benign

0.025

LIST_S2

Benign

0.62

T;T;T;T;.;.

M_CAP

Benign

0.0046

MetaRNN

Benign

0.011

T;T;T;T;T;T

MetaSVM

Benign

-0.93

MutationAssessor

Benign

-1.2

N;N;N;.;N;N

MutationTaster

Benign

1.0

N;N;N;N;N;N

PrimateAI

Benign

0.27

PROVEAN

Benign

0.15

N;N;N;N;N;N

REVEL

Benign

0.028

Sift

Benign

1.0

T;T;T;T;T;T

Sift4G

Benign

1.0

T;T;T;T;T;T

Polyphen

0.0

B;.;B;.;.;B

Vest4

0.21

MVP

0.055

MPC

0.071

ClinPred

0.012

GERP RS

-1.1

Varity_R

0.020

gMVP

0.21

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