rs1057519954

chr3-49375465-T-Achr3-49375465-T-Cchr3-49375465-T-G

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1 PM2 PM5 PP2 PP3_Moderate PP5

The NM_001664.4(RHOA):c.125A>T(p.Tyr42Phe) 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 Likely pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Y42C) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 31)
• Consequence: RHOA NM_001664.4 missense
• Clinical Significance: Likely pathogenic no assertion criteria provided P:3
• Conservation: PhyloP100: 7.87

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]

ACMG classification

Verdict is Pathogenic. Variant got 10 ACMG points.

• PM1: In a strand (size 6) 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
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr3-49375465-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 376522.Status of the report is no_assertion_criteria_provided, 0 stars.
• PP2: Missense variant where missense usually causes diseases, RHOA
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.859
• PP5: Variant 3-49375465-T-A is Pathogenic according to our data. Variant chr3-49375465-T-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 376524.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RHOA	NM_001664.4	c.125A>T	p.Tyr42Phe	missense_variant	2/5	ENST00000418115.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RHOA	ENST00000418115.6	c.125A>T	p.Tyr42Phe	missense_variant	2/5	1	NM_001664.4	P1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:3

Revision: no assertion criteria provided

Submissions by phenotype

Gastric adenocarcinoma Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

May 31, 2016

- -

Non-Hodgkin lymphoma Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

May 31, 2016

- -

Squamous cell carcinoma of the head and neck Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

May 31, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.60
BayesDel_addAF	Uncertain	0.039	T
BayesDel_noAF	Benign	-0.18
Cadd	Uncertain	25
Dann	Uncertain	0.99
DEOGEN2	Uncertain	0.49	T;D;.;T
Eigen	Benign	0.15
Eigen_PC	Uncertain	0.35
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.96	D;D;D;.
M_CAP	Benign	0.015	T
MetaRNN	Pathogenic	0.86	D;D;D;D
MetaSVM	Benign	-0.71	T
MutationAssessor	Benign	0.69	N;.;.;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.90	D
PROVEAN	Uncertain	-3.6	D;D;D;D
REVEL	Uncertain	0.45
Sift	Benign	0.047	D;D;T;T
Sift4G	Uncertain	0.038	D;D;D;D
Polyphen		0.0030	B;.;.;.
Vest4		0.50
MutPred		0.84		Gain of catalytic residue at Y42 (P = 0.0498);Gain of catalytic residue at Y42 (P = 0.0498);Gain of catalytic residue at Y42 (P = 0.0498);Gain of catalytic residue at Y42 (P = 0.0498);
MVP		0.67
MPC		1.7
ClinPred		0.95	D
GERP RS		5.9
Varity_R		0.81
gMVP		0.84

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: rs1057519954; hg19: chr3-49412898; COSMIC: COSV69042190;