3-49375472-C-T

Variant names:

• chr3-49375472-C-T
• rs1057519951
• NM_001664.4:c.118G>A

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM1 PM2 PP2 PP3_Moderate

The NM_001664.4(RHOA):​c.118G>A​(p.Glu40Lys) 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 31)
• Consequence: RHOA NM_001664.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.77
• Publications: 25 publications found

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]

RHOA Gene-Disease associations (from GenCC):

• ectodermal dysplasia with facial dysmorphism and acral, ocular, and brain anomalies

  Inheritance: Unknown Classification: LIMITED Submitted by: Ambry Genetics

ENSG00000290318 (HGNC:):

ACMG classification

Our verdict: Likely_pathogenic. The variant received 7 ACMG points.

• PM1: In a chain Transforming protein RhoA (size 189) in uniprot entity RHOA_HUMAN there are 4 pathogenic changes around while only 0 benign (100%) in NM_001664.4
• 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, 0.859

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001664.4. 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
	RHOA	NM_001664.4	MANE Select	c.118G>A	p.Glu40Lys	missense	Exon 2 of 5	NP_001655.1	P61586
	RHOA	NM_001313941.2		c.118G>A	p.Glu40Lys	missense	Exon 3 of 6	NP_001300870.1	A0A024R324
	RHOA	NM_001313943.2		c.118G>A	p.Glu40Lys	missense	Exon 2 of 6	NP_001300872.1	C9JX21

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RHOA	ENST00000418115.6	TSL:1 MANE Select	c.118G>A	p.Glu40Lys	missense	Exon 2 of 5	ENSP00000400175.1	P61586
	ENSG00000290318	ENST00000704381.1		c.118G>A	p.Glu40Lys	missense	Exon 2 of 6	ENSP00000515884.1	A0A994J514
	RHOA	ENST00000880080.1		c.118G>A	p.Glu40Lys	missense	Exon 2 of 6	ENSP00000550139.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.33	D
BayesDel_noAF	Pathogenic	0.24
CADD	Pathogenic	28
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.50	T
Eigen	Uncertain	0.49
Eigen_PC	Uncertain	0.60
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.97	D
M_CAP	Uncertain	0.11	D
MetaRNN	Pathogenic	0.86	D
MetaSVM	Uncertain	0.099	D
MutationAssessor	Uncertain	2.2	M
PhyloP100		7.8
PrimateAI	Pathogenic	0.93	D
PROVEAN	Uncertain	-3.6	D
REVEL	Pathogenic	0.77
Sift	Uncertain	0.0070	D
Sift4G	Uncertain	0.0020	D
Polyphen		0.11	B
Vest4		0.77
MutPred		0.69		Gain of methylation at E40 (P = 0.0126)
MVP		0.91
MPC		3.1
ClinPred		0.96	D
GERP RS		5.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.95
gMVP		0.94
Mutation Taster		=35/65	disease causing (ClinVar)

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: rs1057519951; hg19: chr3-49412905; COSMIC: COSV69042111;