3-49368502-C-T

Position:

• chr3-49368502-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP2 PP3

The NM_001664.4(RHOA):​c.203G>A​(p.Arg68His) 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. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: RHOA NM_001664.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:2
• Conservation: PhyloP100: 7.75

Genes affected

RHOA (HGNC:667): (ras homolog family member A) 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. Overexpression of this gene is associated with tumor cell proliferation and metastasis. Multiple alternatively spliced variants have been identified. [provided by RefSeq, Sep 2015]

ENSG00000290318 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), RHOA. . Gene score misZ 3.3579 (greater than the threshold 3.09). Trascript score misZ 4.5608 (greater than threshold 3.09). GenCC has associacion of gene with ectodermal dysplasia with facial dysmorphism and acral, ocular, and brain anomalies.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.836

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RHOA	NM_001664.4	c.203G>A	p.Arg68His	missense_variant	3/5	ENST00000418115.6	NP_001655.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RHOA	ENST00000418115.6	c.203G>A	p.Arg68His	missense_variant	3/5	1	NM_001664.4	ENSP00000400175.1
ENSG00000290318	ENST00000704381.1	c.203G>A	p.Arg68His	missense_variant	3/6			ENSP00000515884.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, single submitter

Submissions by phenotype

RHOA-related disorder Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

May 07, 2024

The RHOA c.203G>A variant is predicted to result in the amino acid substitution p.Arg68His. To our knowledge, this variant has not been reported in the literature or in a large population database, indicating this variant is rare. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Nov 26, 2024

De novo variant with confirmed parentage in multiple patients referred for genetic testing at GeneDx; however, the reported clinical features are only partially consistent with the features typically observed in individuals with pathogenic variants in this gene; In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously reported as pathogenic or benign in association with RHOA-related disorders to our knowledge; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 37969960) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.25	D
BayesDel_noAF	Uncertain	0.12
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.51	D;.;D
Eigen	Uncertain	0.27
Eigen_PC	Uncertain	0.43
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.78	T;T;.
M_CAP	Benign	0.038	D
MetaRNN	Pathogenic	0.84	D;D;D
MetaSVM	Benign	-0.33	T
MutationAssessor	Uncertain	2.7	M;.;.
PrimateAI	Pathogenic	0.87	D
PROVEAN	Pathogenic	-4.8	D;D;D
REVEL	Pathogenic	0.66
Sift	Uncertain	0.012	D;D;D
Sift4G	Uncertain	0.038	D;D;D
Polyphen		0.0060	B;.;.
Vest4		0.58
MutPred		0.77		Gain of glycosylation at Y66 (P = 0.0064);Gain of glycosylation at Y66 (P = 0.0064);Gain of glycosylation at Y66 (P = 0.0064);
MVP		0.88
MPC		2.3
ClinPred		0.98	D
GERP RS		5.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.89
gMVP		0.83

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr3-49405935; COSMIC: COSV101371123; COSMIC: COSV101371123;