chr5-73909892-C-G

Variant names:

• chr5-73909892-C-G
• rs17634865
• NM_001177693.2:c.4642C>G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001177693.2(ARHGEF28):​c.4642C>G​(p.Pro1548Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000738 in 1,354,656 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 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. P1548S) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 7.4e-7 (0 hom.)
• Consequence: ARHGEF28 NM_001177693.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.07
• Publications: 0 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: AD, AR, SD Classification: MODERATE, LIMITED Submitted by: Genomics England PanelApp, ClinGen

ENSG00000304540 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.041466087).

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.4642C>G	p.Pro1548Ala	missense	Exon 34 of 36	NP_001171164.1	Q8N1W1-1
	ARHGEF28	NM_001080479.3		c.4642C>G	p.Pro1548Ala	missense	Exon 34 of 37	NP_001073948.2	Q8N1W1-6
	ARHGEF28	NM_001388078.1		c.4642C>G	p.Pro1548Ala	missense	Exon 34 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.4642C>G	p.Pro1548Ala	missense	Exon 34 of 36	ENSP00000441436.1	Q8N1W1-1
	ARHGEF28	ENST00000437974.5	TSL:1	c.4642C>G	p.Pro1548Ala	missense	Exon 33 of 36	ENSP00000411459.1	Q8N1W1-6
	ARHGEF28	ENST00000426542.6	TSL:1	c.4642C>G	p.Pro1548Ala	missense	Exon 33 of 35	ENSP00000412175.2	Q8N1W1-1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 7.38e-7 AC: 1 AN: 1354656 Hom.: 0 Cov.: 30 AF XY: 0.00000150 AC XY: 1 AN XY: 665492

African (AFR) AF: 0.0000333 AC: 1 AN: 30070

American (AMR) AF: 0.00 AC: 0 AN: 29520

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 20170

East Asian (EAS) AF: 0.00 AC: 0 AN: 38768

South Asian (SAS) AF: 0.00 AC: 0 AN: 70124

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 34126

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3988

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1071888

Other (OTH) AF: 0.00 AC: 0 AN: 56002

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.062
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.66
CADD	Benign	0.0030
DANN	Benign	0.28
DEOGEN2	Benign	0.0029	T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.048	N
LIST_S2	Benign	0.19	T
M_CAP	Benign	0.0062	T
MetaRNN	Benign	0.041	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.34	N
PhyloP100		-1.1
PrimateAI	Benign	0.24	T
PROVEAN	Benign	-0.57	N
REVEL	Benign	0.0070
Sift	Benign	0.90	T
Sift4G	Benign	0.74	T
Polyphen		0.0070	B
Vest4		0.14
MutPred		0.23		Loss of disorder (P = 0.0595)
MVP		0.040
MPC		0.068
ClinPred		0.026	T
GERP RS		-4.5
Varity_R		0.011
gMVP		0.082
Mutation Taster		=98/2	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

Other links and lift over

dbSNP: rs17634865; hg19: chr5-73205717;