Genetic Variant ARHGEF28:p.Met84Leu (chr5-73752977-A-T) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001177693.2(ARHGEF28):c.250A>T(p.Met84Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,534 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 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. M84R) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

ARHGEF28
NM_001177693.2 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.36

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: AR, AD, SD Classification: MODERATE, LIMITED Submitted by: Genomics England PanelApp, ClinGen

ARHGEF28 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.07952681).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001177693.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ARHGEF28	NM_001177693.2	MANE Select	c.250A>T	p.Met84Leu	missense	Exon 4 of 36	NP_001171164.1	Q8N1W1-1
ARHGEF28	NM_001080479.3		c.250A>T	p.Met84Leu	missense	Exon 4 of 37	NP_001073948.2	Q8N1W1-6
ARHGEF28	NM_001388078.1		c.250A>T	p.Met84Leu	missense	Exon 4 of 35	NP_001375007.1	Q8N1W1-4

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ARHGEF28	ENST00000513042.7	TSL:5 MANE Select	c.250A>T	p.Met84Leu	missense	Exon 4 of 36	ENSP00000441436.1	Q8N1W1-1
ARHGEF28	ENST00000437974.5	TSL:1	c.250A>T	p.Met84Leu	missense	Exon 3 of 36	ENSP00000411459.1	Q8N1W1-6
ARHGEF28	ENST00000426542.6	TSL:1	c.250A>T	p.Met84Leu	missense	Exon 3 of 35	ENSP00000412175.2	Q8N1W1-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461534

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727022

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33478

American (AMR)

AF:

0.00

AC:

AN:

44702

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26132

East Asian (EAS)

AF:

0.00

AC:

AN:

39698

South Asian (SAS)

AF:

0.00

AC:

AN:

86184

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53402

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

8.99e-7

AC:

AN:

1111798

Other (OTH)

AF:

0.00

AC:

AN:

60372

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

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 v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.19

BayesDel_addAF

Benign

-0.18

BayesDel_noAF

Benign

-0.49

CADD

Benign

(source)

DANN

Benign

0.94

DEOGEN2

Benign

0.0032

Eigen

Benign

-0.35

Eigen_PC

Benign

-0.13

FATHMM_MKL

Benign

0.66

LIST_S2

Benign

0.68

M_CAP

Benign

0.0026

MetaRNN

Benign

0.080

MetaSVM

Benign

-0.95

MutationAssessor

Benign

1.7

PhyloP100

1.4

PrimateAI

Uncertain

0.48

PROVEAN

Benign

-0.48

REVEL

Benign

0.078

Sift

Benign

0.48

Sift4G

Benign

1.0

Polyphen

0.0040

Vest4

0.17

MutPred

0.30

Gain of catalytic residue at M84 (P = 0.086)

MVP

0.12

MPC

0.066

ClinPred

0.22

GERP RS

4.7

Varity_R

0.091

gMVP

0.20

Mutation Taster

=85/15

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over