NM_001177693.2:c.1754G>C

Variant names:

• chr5-73852656-G-C
• rs2973566
• NM_001177693.2:c.1754G>C
• ARHGEF28 p.Arg585Thr

Variant summary

Our verdict is Uncertain significance. The variant received 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 Benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ARHGEF28 NM_001177693.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.54
• Publications: 28 publications found

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

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

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

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ARHGEF28	NM_001177693.2	MANE Select	c.1754G>C	p.Arg585Thr	missense	Exon 14 of 36	NP_001171164.1	Q8N1W1-1
	ARHGEF28	NM_001080479.3		c.1754G>C	p.Arg585Thr	missense	Exon 14 of 37	NP_001073948.2	Q8N1W1-6
	ARHGEF28	NM_001388078.1		c.1754G>C	p.Arg585Thr	missense	Exon 14 of 35	NP_001375007.1	Q8N1W1-4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ARHGEF28	ENST00000513042.7	TSL:5 MANE Select	c.1754G>C	p.Arg585Thr	missense	Exon 14 of 36	ENSP00000441436.1	Q8N1W1-1
	ARHGEF28	ENST00000437974.5	TSL:1	c.1754G>C	p.Arg585Thr	missense	Exon 13 of 36	ENSP00000411459.1	Q8N1W1-6
	ARHGEF28	ENST00000426542.6	TSL:1	c.1754G>C	p.Arg585Thr	missense	Exon 13 of 35	ENSP00000412175.2	Q8N1W1-1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 24618

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

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
Eigen	Pathogenic	0.84
Eigen_PC	Pathogenic	0.85
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.90	D
M_CAP	Benign	0.013	T
MetaRNN	Uncertain	0.70	D
MetaSVM	Benign	-0.99	T
MutationAssessor	Uncertain	2.6	M
PhyloP100		6.5
PrimateAI	Uncertain	0.53	T
PROVEAN	Benign	-2.0	N
REVEL	Benign	0.21
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.0080	D
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.19
gMVP		0.55
Mutation Taster		=84/16	polymorphism

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs2973566;

hg19: chr5-73148481;