Genetic Variant ARHGEF28:p.Pro284Leu (chr5-73780686-C-T) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_001177693.2(ARHGEF28):c.851C>T(p.Pro284Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P284Q) has been classified as Benign.

Frequency

Genomes: not found (cov: 30)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

ARHGEF28
NM_001177693.2 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.90

Publications

36 publications found

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 Gene-Disease associations (from GenCC):

amyotrophic lateral sclerosis
Inheritance: AD, AR Classification: MODERATE Submitted by: Genomics England PanelApp

ARHGEF28 links:

ENSG00000249293 (HGNC:):

ENSG00000249293 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.04796645).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
ARHGEF28	NM_001177693.2 link	c.851C>T	p.Pro284Leu	missense_variant	Exon 7 of 36	ENST00000513042.7	NP_001171164.1
ARHGEF28	NM_001080479.3 link	c.851C>T	p.Pro284Leu	missense_variant	Exon 7 of 37		NP_001073948.2
ARHGEF28	NM_001388078.1 link	c.851C>T	p.Pro284Leu	missense_variant	Exon 7 of 35		NP_001375007.1
ARHGEF28	NM_001388076.1 link	c.557C>T	p.Pro186Leu	missense_variant	Exon 6 of 35		NP_001375005.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ARHGEF28	ENST00000513042.7 link	c.851C>T	p.Pro284Leu	missense_variant	Exon 7 of 36	5	NM_001177693.2	ENSP00000441436.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1403194

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

692480

African (AFR)

AF:

0.00

AC:

AN:

31766

American (AMR)

AF:

0.00

AC:

AN:

36168

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25220

East Asian (EAS)

AF:

0.00

AC:

AN:

36130

South Asian (SAS)

AF:

0.00

AC:

AN:

79428

European-Finnish (FIN)

AF:

0.00

AC:

AN:

49404

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5696

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1081176

Other (OTH)

AF:

0.00

AC:

AN:

58206

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

87058

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.071

BayesDel_addAF

Benign

-0.33

BayesDel_noAF

Benign

-0.71

CADD

Benign

(source)

DANN

Benign

0.92

DEOGEN2

Benign

0.0032

.;.;T;.;T

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.33

LIST_S2

Benign

0.27

T;T;T;.;.

M_CAP

Benign

0.0047

MetaRNN

Benign

0.048

T;T;T;T;T

MetaSVM

Benign

-0.95

MutationAssessor

Benign

0.0

N;N;N;N;N

PhyloP100

1.9

PrimateAI

Benign

0.28

PROVEAN

Benign

-0.88

N;N;N;N;N

REVEL

Benign

0.082

Sift

Benign

0.26

T;T;T;T;T

Sift4G

Benign

0.20

T;T;T;T;T

Polyphen

0.0010

B;.;B;.;B

Vest4

0.054

MutPred

0.27

Gain of helix (P = 0.0082);Gain of helix (P = 0.0082);Gain of helix (P = 0.0082);Gain of helix (P = 0.0082);Gain of helix (P = 0.0082);

MVP

0.12

MPC

0.071

ClinPred

0.073

GERP RS

-0.022

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.047

gMVP

0.16

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over