11-3828104-C-T

Position:

• chr11-3828104-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The ENST00000351018.5(RHOG):​c.35G>A​(p.Gly12Glu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: RHOG ENST00000351018.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.91

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.981

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RHOG	NM_001665.4	c.35G>A	p.Gly12Glu	missense_variant	2/2	ENST00000351018.5	NP_001656.2
RHOG	XM_005252916.3	c.35G>A	p.Gly12Glu	missense_variant	2/2		XP_005252973.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RHOG	ENST00000351018.5	c.35G>A	p.Gly12Glu	missense_variant	2/2	1	NM_001665.4	ENSP00000339467	P1
RHOG	ENST00000396978.1	c.35G>A	p.Gly12Glu	missense_variant	2/2	3		ENSP00000380175	P1
RHOG	ENST00000396979.1	c.35G>A	p.Gly12Glu	missense_variant	2/2	3		ENSP00000380176	P1
RHOG	ENST00000533217.1	c.35G>A	p.Gly12Glu	missense_variant	2/2	5		ENSP00000436932	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 29, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.43	D
BayesDel_noAF	Pathogenic	0.38
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.53	D;D;D;D
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.98
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.94	.;.;.;D
M_CAP	Pathogenic	0.39	D
MetaRNN	Pathogenic	0.98	D;D;D;D
MetaSVM	Pathogenic	0.81	D
MutationAssessor	Pathogenic	3.3	M;M;M;M
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Pathogenic	0.94	D
PROVEAN	Pathogenic	-7.2	D;D;D;D
REVEL	Pathogenic	0.92
Sift	Pathogenic	0.0	D;D;D;D
Sift4G	Uncertain	0.0070	D;D;D;D
Polyphen		1.0	D;D;D;D
Vest4		0.86
MutPred		0.92		Gain of methylation at K16 (P = 0.1178);Gain of methylation at K16 (P = 0.1178);Gain of methylation at K16 (P = 0.1178);Gain of methylation at K16 (P = 0.1178);
MVP		0.89
MPC		2.7
ClinPred		1.0	D
GERP RS		5.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.95
gMVP		0.98

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: rs2090096385; hg19: chr11-3849334;