5-73753022-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_001177693.2(ARHGEF28):​c.295C>G​(p.Leu99Val) 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. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Consequence

ARHGEF28
NM_001177693.2 missense

Scores

5
14

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.108
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]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.28992593).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
ARHGEF28NM_001177693.2 linkc.295C>G p.Leu99Val missense_variant Exon 4 of 36 ENST00000513042.7 NP_001171164.1 Q8N1W1-1
ARHGEF28NM_001080479.3 linkc.295C>G p.Leu99Val missense_variant Exon 4 of 37 NP_001073948.2 Q8N1W1-6
ARHGEF28NM_001388078.1 linkc.295C>G p.Leu99Val missense_variant Exon 4 of 35 NP_001375007.1
ARHGEF28NM_001388076.1 linkc.181+3038C>G intron_variant Intron 3 of 34 NP_001375005.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
ARHGEF28ENST00000513042.7 linkc.295C>G p.Leu99Val missense_variant Exon 4 of 36 5 NM_001177693.2 ENSP00000441436.1 Q8N1W1-1

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
Cov.:
31
GnomAD4 genome
Cov.:
33

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Dec 17, 2024
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.295C>G (p.L99V) alteration is located in exon 4 (coding exon 3) of the ARHGEF28 gene. This alteration results from a C to G substitution at nucleotide position 295, causing the leucine (L) at amino acid position 99 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.19
BayesDel_addAF
Benign
-0.17
T
BayesDel_noAF
Benign
-0.48
CADD
Benign
19
DANN
Uncertain
1.0
DEOGEN2
Benign
0.010
.;.;T;.;T
Eigen
Uncertain
0.23
Eigen_PC
Uncertain
0.24
FATHMM_MKL
Benign
0.73
D
LIST_S2
Benign
0.80
T;T;T;.;.
M_CAP
Benign
0.0057
T
MetaRNN
Benign
0.29
T;T;T;T;T
MetaSVM
Benign
-1.1
T
MutationAssessor
Uncertain
2.2
M;M;M;M;M
PrimateAI
Uncertain
0.51
T
PROVEAN
Benign
-0.27
N;N;N;N;N
REVEL
Benign
0.14
Sift
Benign
0.23
T;T;T;T;T
Sift4G
Benign
0.29
T;T;T;T;T
Polyphen
0.98
D;.;D;.;D
Vest4
0.53
MutPred
0.28
Gain of catalytic residue at L99 (P = 0.0111);Gain of catalytic residue at L99 (P = 0.0111);Gain of catalytic residue at L99 (P = 0.0111);Gain of catalytic residue at L99 (P = 0.0111);Gain of catalytic residue at L99 (P = 0.0111);
MVP
0.29
MPC
0.31
ClinPred
0.48
T
GERP RS
4.0
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.050
gMVP
0.37

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.050
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr5-73048847; API