rs1456489348

Variant names:

• chr11-3827717-T-C
• rs1456489348
• NM_001665.4:c.422A>G

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001665.4(RHOG):​c.422A>G​(p.Gln141Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,752 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q141K) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: RHOG NM_001665.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.02
• Publications: 0 publications found

Genes affected

RHOG (HGNC:672): (ras homolog family member G) This gene encodes a member of the Rho family of small GTPases, which cycle between inactive GDP-bound and active GTP-bound states and function as molecular switches in signal transduction cascades. Rho proteins promote reorganization of the actin cytoskeleton and regulate cell shape, attachment, and motility. The encoded protein facilitates translocation of a functional guanine nucleotide exchange factor (GEF) complex from the cytoplasm to the plasma membrane where ras-related C3 botulinum toxin substrate 1 is activated to promote lamellipodium formation and cell migration. Two related pseudogene have been identified on chromosomes 20 and X. [provided by RefSeq, Aug 2011]

RHOG Gene-Disease associations (from GenCC):

• hemophagocytic lymphohistiocytosis due to RhoG deficiency

  Inheritance: AR Classification: MODERATE Submitted by: ClinGen

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_001665.4. 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
	RHOG	NM_001665.4	MANE Select	c.422A>G	p.Gln141Arg	missense	Exon 2 of 2	NP_001656.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RHOG	ENST00000351018.5	TSL:1 MANE Select	c.422A>G	p.Gln141Arg	missense	Exon 2 of 2	ENSP00000339467.4	P84095
	RHOG	ENST00000396978.1	TSL:3	c.422A>G	p.Gln141Arg	missense	Exon 2 of 2	ENSP00000380175.1	P84095
	RHOG	ENST00000396979.1	TSL:3	c.422A>G	p.Gln141Arg	missense	Exon 2 of 2	ENSP00000380176.1	P84095

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000399 AC: 1 AN: 250418 AF XY: 0.00000738

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: 0.00

Gnomad OTH exome AF: 0.000164

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461752 Hom.: 0 Cov.: 31 AF XY: 0.00000413 AC XY: 3 AN XY: 727196

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26124

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86252

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53320

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000270 AC: 3 AN: 1111998

Other (OTH) AF: 0.0000166 AC: 1 AN: 60396

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.63
BayesDel_addAF	Uncertain	0.082	D
BayesDel_noAF	Benign	-0.12
CADD	Pathogenic	30
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.53	D
Eigen	Uncertain	0.27
Eigen_PC	Uncertain	0.40
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.93	D
M_CAP	Benign	0.053	D
MetaRNN	Uncertain	0.47	T
MetaSVM	Uncertain	-0.17	T
MutationAssessor	Benign	2.0	M
PhyloP100		8.0
PrimateAI	Uncertain	0.71	T
PROVEAN	Uncertain	-3.5	D
REVEL	Uncertain	0.59
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.047	D
Polyphen		0.028	B
Vest4		0.55
MutPred		0.49		Gain of MoRF binding (P = 0.0311)
MVP		0.86
MPC		2.5
ClinPred		0.94	D
GERP RS		5.5
Varity_R		0.91
gMVP		0.87
Mutation Taster		=45/55	disease causing

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: rs1456489348; hg19: chr11-3848947;