5-73753022-C-G

Variant names:

• chr5-73753022-C-G
• NM_001177693.2:c.295C>G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

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
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.108

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]

ACMG classification

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
ARHGEF28	NM_001177693.2	c.295C>G	p.Leu99Val	missense_variant	Exon 4 of 36	ENST00000513042.7	NP_001171164.1
ARHGEF28	NM_001080479.3	c.295C>G	p.Leu99Val	missense_variant	Exon 4 of 37		NP_001073948.2
ARHGEF28	NM_001388078.1	c.295C>G	p.Leu99Val	missense_variant	Exon 4 of 35		NP_001375007.1
ARHGEF28	NM_001388076.1	c.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
ARHGEF28	ENST00000513042.7	c.295C>G	p.Leu99Val	missense_variant	Exon 4 of 36	5	NM_001177693.2	ENSP00000441436.1

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

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;