3-49375451-C-T

Position:

• chr3-49375451-C-T

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM2 PP2 PP3 PP5_Very_Strong

The NM_001664.4(RHOA):​c.139G>A​(p.Glu47Lys) 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 Pathogenic (★★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: RHOA NM_001664.4 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:8
• Conservation: PhyloP100: 7.76

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 Pathogenic. Variant got 12 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the RHOA gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 12 curated pathogenic missense variants (we use a threshold of 10). The gene has 1 curated benign missense variants. Gene score misZ: 3.3579 (above the threshold of 3.09). Trascript score misZ: 4.5608 (above the threshold of 3.09). GenCC associations: The gene is linked to ectodermal dysplasia with facial dysmorphism and acral, ocular, and brain anomalies.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.768
• PP5: Variant 3-49375451-C-T is Pathogenic according to our data. Variant chr3-49375451-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 695069.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RHOA	NM_001664.4	c.139G>A	p.Glu47Lys	missense_variant	2/5	ENST00000418115.6	NP_001655.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RHOA	ENST00000418115.6	c.139G>A	p.Glu47Lys	missense_variant	2/5	1	NM_001664.4	ENSP00000400175.1
ENSG00000290318	ENST00000704381.1	c.139G>A	p.Glu47Lys	missense_variant	2/6			ENSP00000515884.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Ectodermal dysplasia with facial dysmorphism and acral, ocular, and brain anomalies Pathogenic:4

Pathogenic, no assertion criteria provided	literature only	OMIM	Jan 29, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Equipe Genetique des Anomalies du Developpement, Université de Bourgogne	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Nov 06, 2022	- -
Pathogenic, no assertion criteria provided	clinical testing	Undiagnosed Diseases Network, NIH	Feb 14, 2023	- -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Oct 05, 2023	This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 47 of the RHOA protein (p.Glu47Lys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with RHOA-related conditions (PMID: 31570889, 31821646). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 695069). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects RHOA function (PMID: 31570889). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Nov 25, 2022	Identified in multiple unrelated patients as a somatic mosaic variant in skin tissue with hypopigmented areas of the skin, dental anomalies, body asymmetry, hemihypotrophy and brain magnetic resonance imaging (MRI) anomalies in published literature (Vabres et al., 2019; Yigit et al., 2019); Published functional studies demonstrate a inactivating effect of the Glu47Lys RHOA variant (Vabres et al., 2019); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 31570889, 31821646, 32335911) -

Hemihypertrophy Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Equipe Genetique des Anomalies du Developpement, Université de Bourgogne

-

- -

neuro-ectodermal phenotype Pathogenic:1

Pathogenic, criteria provided, single submitter

research

Institute of Human Genetics, University of Goettingen

Nov 28, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.75
BayesDel_addAF	Pathogenic	0.35	D
BayesDel_noAF	Pathogenic	0.26
CADD	Pathogenic	33
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.48	T;T;.;T
Eigen	Pathogenic	0.70
Eigen_PC	Pathogenic	0.75
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	D;D;D;.
M_CAP	Benign	0.046	D
MetaRNN	Pathogenic	0.77	D;D;D;D
MetaSVM	Uncertain	-0.011	T
MutationAssessor	Benign	0.29	N;.;.;.
PrimateAI	Pathogenic	0.93	D
PROVEAN	Uncertain	-3.6	D;D;D;D
REVEL	Pathogenic	0.74
Sift	Uncertain	0.010	D;D;D;D
Sift4G	Benign	0.32	T;T;T;T
Polyphen		1.0	D;.;.;.
Vest4		0.74
MutPred		0.52		Gain of ubiquitination at E47 (P = 0.0311);Gain of ubiquitination at E47 (P = 0.0311);Gain of ubiquitination at E47 (P = 0.0311);Gain of ubiquitination at E47 (P = 0.0311);
MVP		0.88
MPC		3.1
ClinPred		0.95	D
GERP RS		5.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.87
gMVP		0.80

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: rs1575653629; hg19: chr3-49412884; COSMIC: COSV69041798;