5-73852656-G-C

Position:

• chr5-73852656-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001177693.2(ARHGEF28):​c.1754G>C​(p.Arg585Thr) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. 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. R585K) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ARHGEF28 NM_001177693.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.54

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ARHGEF28	NM_001177693.2	c.1754G>C	p.Arg585Thr	missense_variant	14/36	ENST00000513042.7	NP_001171164.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ARHGEF28	ENST00000513042.7	c.1754G>C	p.Arg585Thr	missense_variant	14/36	5	NM_001177693.2	ENSP00000441436.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Benign	-0.050	T
BayesDel_noAF	Benign	-0.31
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.11	.;.;T;.;T;.
Eigen	Pathogenic	0.84
Eigen_PC	Pathogenic	0.85
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.90	D;D;D;.;.;D
M_CAP	Benign	0.013	T
MetaRNN	Uncertain	0.70	D;D;D;D;D;D
MetaSVM	Benign	-0.99	T
MutationAssessor	Uncertain	2.6	M;M;M;M;M;.
PrimateAI	Uncertain	0.53	T
PROVEAN	Benign	-2.0	N;N;N;N;N;N
REVEL	Benign	0.21
Sift	Uncertain	0.0030	D;D;D;D;D;D
Sift4G	Uncertain	0.0080	D;D;D;D;D;D
Polyphen		1.0	D;.;D;.;D;.
Vest4		0.57
MutPred		0.17		Gain of phosphorylation at R585 (P = 0.0298);Gain of phosphorylation at R585 (P = 0.0298);Gain of phosphorylation at R585 (P = 0.0298);Gain of phosphorylation at R585 (P = 0.0298);Gain of phosphorylation at R585 (P = 0.0298);.;
MVP		0.53
MPC		0.50
ClinPred		0.88	D
GERP RS		6.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.19
gMVP		0.55

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

LitVar

Other links and lift over

dbSNP: rs2973566; hg19: chr5-73148481;