rs773215317

Variant names:

• chr2-131040098-C-G
• rs773215317
• NM_001367493.1:c.4388C>G

Your query was ambiguous. Multiple possible variants found:

• chr2-131040098-C-G
• chr2-131040098-C-T

Variant summary

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

The NM_001367493.1(ARHGEF4):​c.4388C>G​(p.Ala1463Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000686 in 1,457,742 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 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. A1463V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: ARHGEF4 NM_001367493.1 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.903
• Publications: 0 publications found

Genes affected

ARHGEF4 (HGNC:684): (Rho guanine nucleotide exchange factor 4) Rho GTPases play a fundamental role in numerous cellular processes that are initiated by extracellular stimuli that work through G protein coupled receptors. The protein encoded by this gene may form complex with G proteins and stimulate Rho-dependent signals. Multiple alternatively spliced transcript variants encoding different isoforms have been found, but the full-length nature of some variants has not been determined. [provided by RefSeq, Jun 2013]

SMIM39 (HGNC:54076): (small integral membrane protein 39) Predicted to be integral component of membrane. [provided by Alliance of Genome Resources, Apr 2022]

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=0.06421384).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001367493.1. 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
	ARHGEF4	NM_001367493.1	MANE Select	c.4388C>G	p.Ala1463Gly	missense	Exon 7 of 14	NP_001354422.1	E7EV07
	ARHGEF4	NM_001375900.1		c.875C>G	p.Ala292Gly	missense	Exon 6 of 13	NP_001362829.1
	ARHGEF4	NM_015320.4		c.830C>G	p.Ala277Gly	missense	Exon 8 of 15	NP_056135.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ARHGEF4	ENST00000409359.7	TSL:5 MANE Select	c.4388C>G	p.Ala1463Gly	missense	Exon 7 of 14	ENSP00000386794.3	E7EV07
	ARHGEF4	ENST00000392953.8	TSL:1	c.902C>G	p.Ala301Gly	missense	Exon 6 of 12	ENSP00000376680.5	A0A0C4DFY6
	ARHGEF4	ENST00000355771.7	TSL:1	c.617C>G	p.Ala206Gly	missense	Exon 4 of 11	ENSP00000348017.3	Q9NR80-3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000409 AC: 1 AN: 244250 AF XY: 0.00000754

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000913

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.86e-7 AC: 1 AN: 1457742 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 725034

African (AFR) AF: 0.00 AC: 0 AN: 33378

American (AMR) AF: 0.00 AC: 0 AN: 44424

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26082

East Asian (EAS) AF: 0.00 AC: 0 AN: 39510

South Asian (SAS) AF: 0.00 AC: 0 AN: 85918

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52580

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 9.01e-7 AC: 1 AN: 1109890

Other (OTH) AF: 0.00 AC: 0 AN: 60194

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.00000825 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.069
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	12
DANN	Uncertain	0.98
DEOGEN2	Benign	0.0050	T
Eigen	Benign	-0.80
Eigen_PC	Benign	-0.74
FATHMM_MKL	Benign	0.21	N
LIST_S2	Benign	0.71	T
M_CAP	Benign	0.048	D
MetaRNN	Benign	0.064	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.0	L
PhyloP100		0.90
PrimateAI	Uncertain	0.53	T
PROVEAN	Benign	-1.0	N
REVEL	Benign	0.052
Sift	Benign	0.20	T
Sift4G	Benign	0.53	T
Polyphen		0.0010	B
Vest4		0.16
MutPred		0.11		Gain of loop (P = 0.2045)
MVP		0.70
MPC		0.12
ClinPred		0.072	T
GERP RS		3.0
Varity_R		0.14
gMVP		0.44
Mutation Taster		=96/4	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: rs773215317; hg19: chr2-131797671;