rs1057519952

Variant names:

• chr3-49375577-G-A
• rs1057519952
• NM_001664.4:c.13C>T

Your query was ambiguous. Multiple possible variants found:

• chr3-49375577-G-A
• chr3-49375577-G-C
• chr3-49375577-G-T

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM1 PM2 PP2

The NM_001664.4(RHOA):​c.13C>T​(p.Arg5Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as (no stars).

• Frequency: Genomes: not found (cov: 31)
• Consequence: RHOA NM_001664.4 missense
• Clinical Significance: - - O:1
• Conservation: PhyloP100: 1.34
• Publications: 27 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: Uncertain_significance. The variant received 5 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RHOA	NM_001664.4	c.13C>T	p.Arg5Trp	missense_variant	Exon 2 of 5	ENST00000418115.6	NP_001655.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RHOA	ENST00000418115.6	c.13C>T	p.Arg5Trp	missense_variant	Exon 2 of 5	1	NM_001664.4	ENSP00000400175.1
ENSG00000290318	ENST00000704381.1	c.13C>T	p.Arg5Trp	missense_variant	Exon 2 of 6			ENSP00000515884.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

ClinVar

Significance: -

Submissions summary: Other:1

Revision: -

Submissions by phenotype

Neoplasm Other:1

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance: -

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.27	D
BayesDel_noAF	Pathogenic	0.14
CADD	Uncertain	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.20	T;T;.;T
Eigen	Benign	-0.45
Eigen_PC	Benign	-0.39
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.91	D;D;D;.
M_CAP	Benign	0.039	D
MetaRNN	Uncertain	0.74	D;D;D;D
MetaSVM	Benign	-0.57	T
MutationAssessor	Pathogenic	3.1	M;.;.;.
PhyloP100		1.3
PrimateAI	Pathogenic	0.92	D
PROVEAN	Pathogenic	-6.9	D;D;D;D
REVEL	Uncertain	0.33
Sift	Uncertain	0.013	D;D;D;D
Sift4G	Pathogenic	0.0010	D;D;D;D
Polyphen		0.11	B;.;.;.
Vest4		0.77
MutPred		0.57		Loss of disorder (P = 8e-04);Loss of disorder (P = 8e-04);Loss of disorder (P = 8e-04);Loss of disorder (P = 8e-04);
MVP		0.82
MPC		1.8
ClinPred		0.97	D
GERP RS		-0.78
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.87
gMVP		0.90
Mutation Taster		=48/52	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: rs1057519952; hg19: chr3-49413010; COSMIC: COSV69041759;