3-49360288-C-T

Position:

• chr3-49360288-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2 PP2 BP4

The NM_001664.4(RHOA):​c.503G>A​(p.Arg168Lys) 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 benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: RHOA NM_001664.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.88

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 2 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.
• BP4: Computational evidence support a benign effect (MetaRNN=0.37285176).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RHOA	NM_001664.4	c.503G>A	p.Arg168Lys	missense_variant	5/5	ENST00000418115.6	NP_001655.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RHOA	ENST00000418115.6	c.503G>A	p.Arg168Lys	missense_variant	5/5	1	NM_001664.4	ENSP00000400175.1
ENSG00000290318	ENST00000704381.1	c.464+39G>A		intron_variant				ENSP00000515884.1

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

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Oct 05, 2023

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.35
BayesDel_addAF	Uncertain	0.086	D
BayesDel_noAF	Benign	-0.11
CADD	Pathogenic	27
DANN	Uncertain	0.99
DEOGEN2	Benign	0.28	T
Eigen	Benign	0.012
Eigen_PC	Uncertain	0.27
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.93	D
M_CAP	Benign	0.033	D
MetaRNN	Benign	0.37	T
MetaSVM	Benign	-0.80	T
MutationAssessor	Benign	-0.88	N
PrimateAI	Pathogenic	0.86	D
PROVEAN	Benign	-2.2	N
REVEL	Benign	0.26
Sift	Benign	0.11	T
Sift4G	Benign	1.0	T
Polyphen		0.039	B
Vest4		0.55
MutPred		0.38		Gain of methylation at R168 (P = 0.0054);
MVP		0.78
MPC		1.8
ClinPred		0.89	D
GERP RS		6.0
Varity_R		0.61
gMVP		0.92

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr3-49397721;