Genetic Variant ARHGEF28:p.Pro1548Ala (chr5-73909892-C-G) – 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.4642C>G(p.Pro1548Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000738 in 1,354,656 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. P1548S) has been classified as Benign.

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 7.4e-7 ( 0 hom. )

Consequence

ARHGEF28
NM_001177693.2 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -1.07

Publications

0 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:

ENSG00000304540 (HGNC:):

ENSG00000304540 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=0.041466087).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ARHGEF28	NM_001177693.2 link	c.4642C>G	p.Pro1548Ala	missense_variant	Exon 34 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.4642C>G	p.Pro1548Ala	missense_variant	Exon 34 of 36	5	NM_001177693.2	ENSP00000441436.1		Q8N1W1-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.38e-7

AC:

AN:

1354656

Hom.:

Cov.:

AF XY:

0.00000150

AC XY:

AN XY:

665492

show subpopulations

African (AFR)

AF:

0.0000333

AC:

AN:

30070

American (AMR)

AF:

0.00

AC:

AN:

29520

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

20170

East Asian (EAS)

AF:

0.00

AC:

AN:

38768

South Asian (SAS)

AF:

0.00

AC:

AN:

70124

European-Finnish (FIN)

AF:

0.00

AC:

AN:

34126

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3988

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1071888

Other (OTH)

AF:

0.00

AC:

AN:

56002

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.062

BayesDel_addAF

Benign

-0.30

BayesDel_noAF

Benign

-0.66

CADD

Benign

0.0030

(source)

DANN

Benign

0.28

DEOGEN2

Benign

0.0029

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

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.4

FATHMM_MKL

Benign

0.048

LIST_S2

Benign

0.19

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

M_CAP

Benign

0.0062

MetaRNN

Benign

0.041

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

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.34

N;N;N;N;N;.;.

PhyloP100

-1.1

PrimateAI

Benign

0.24

PROVEAN

Benign

-0.57

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

REVEL

Benign

0.0070

Sift

Benign

0.90

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

Sift4G

Benign

0.74

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

Polyphen

0.0070

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

Vest4

0.14

MutPred

0.23

Loss of disorder (P = 0.0595);Loss of disorder (P = 0.0595);Loss of disorder (P = 0.0595);Loss of disorder (P = 0.0595);Loss of disorder (P = 0.0595);.;.;

MVP

0.040

MPC

0.068

ClinPred

0.026

GERP RS

-4.5

Varity_R

0.011

gMVP

0.082

Mutation Taster

=98/2

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over