Variant classification summary

NM_001664.4:c.50G>T

RHOA · NP_001655.1:p.(Gly17Val) · NM_001664.4

GRCh37: chr3:49412973 C>A · GRCh38: chr3:49375540 C>A

Gene: RHOA Transcript: NM_001664.4

Final call

Pathogenic

PS3 strong PM1 moderate PM2 supporting PP3 strong

Variant details

Gene

RHOA

Transcript

NM_001664.4

Protein

NP_001655.1:p.(Gly17Val)

gnomAD AF

ClinVar

Pathogenic

OncoKB

Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

1

Pathogenic: PS3 strong functional assays showed impaired RHOA p.Gly17Val activity and signaling.

2

Pathogenic: PM1 moderate places Gly17 in a statistically significant mutational hotspot without benign variation.

3

Pathogenic: PM2 supporting reflects the variant's absence from evaluated gnomAD datasets.

4

Pathogenic: PP3 strong is supported by REVEL 0.952.

Final determination: Generic ACMG/AMP 2015 fallback rules support Pathogenic when the applied strong, moderate, and supporting pathogenic evidence satisfies the derived combination with higher strengths counting toward lower-strength requirements.

Criteria assessment

ACMG/AMP criteria review

Criteria shown when status is available

All criteria require review: For research and educational purposes only.

Criterion	Status	Rationale	Evidence used
PVS1	N/A	Not applicable: PVS1 requires a null variant (nonsense, frameshift, canonical splice, start-loss or stop-loss), and this is a missense variant.	pvs1_generic_framework generic_acmg_combination_rules
PS1	Not assessed	Not assessed: the record confirms p.Gly17Val but does not verify a pathogenic p.Gly17Val produced by a different nucleotide change.	PMID:24413734 PMID:24584070 spliceai
PS2	Not assessed	Not assessed: no documented germline proband with confirmed maternity and paternity, compatible disease, and absent family history was available.
PS3	Met	Met, strong: independent biochemical and cellular assays showed RHOA p.Gly17Val lost GTPase activity and altered signaling versus wild-type controls.	PMID:24413734 PMID:24584070
PS4	Not assessed	Not assessed: affected-cohort counts exist, but no unaffected or population-control counts permit the required OR/RR >5.0 and confidence interval excluding 1.0.	PMID:24413734 PMID:24584070 PMID:24413737 PMID:22918138 PMID:34131312
PM1	Met	Met: residue G17 is reported in a statistically significant Cancer Hotspots hotspot, and the variant is absent from gnomAD v2.1 and v4.1.	hotspots gnomad_v2 gnomad_v4
PM2	Met	Met at Supporting: the variant is absent from gnomAD v2.1, v4.1, and non-cancer datasets, satisfying the <=0.0001 PM2 frequency threshold.	gnomad_v2 gnomad_v4
PM3	Not assessed	Not assessed: no recessive inheritance context, affected-proband evidence, or parental/offspring phase establishes a pathogenic variant in trans.	clinvar PMID:24413734 PMID:24584070
PM4	N/A	Not applicable: PM4 requires a protein-length change, and this is a missense variant.	pvs1_generic_framework generic_acmg_combination_rules
PM5	Not assessed	Not assessed: p.Gly17Glu is reported at the same residue, but its pathogenic determination is not established by the available evidence.	PMID:24413734 clinvar
PM6	Not assessed	Not assessed: no germline assumed-de novo observation was documented, regardless of whether maternity or paternity confirmation was available.
PP1	Not assessed	Not assessed: no affected relatives with variant testing or documented informative meioses were available to evaluate co-segregation.
PP2	Not assessed	Not assessed: no gene-level evidence establishes both low benign missense variation and a common missense disease mechanism for RHOA.
PP3	Met	Met, strong: REVEL 0.952 meets the generic PP3 strong threshold of >=0.932 for missense variants.	revel
PP4	Not assessed	Not assessed: no individual phenotype or family history is available to establish a highly specific disease phenotype with a single genetic etiology.
PP5	Not met	Not met: ClinVar lists Pathogenic with zero stars and no expert-panel submission, so the required reputable expert-panel assertion is absent.	clinvar
BA1	Not met	Not met: the variant is absent from gnomAD v2.1 and v4.1, providing no filtering allele frequency or grpmax FAF at the >=0.05 BA1 threshold.	gnomad_v2 gnomad_v4
BS1	Not met	Not met: the variant is absent from all reported gnomAD datasets, so no filtering allele frequency or grpmax FAF exceeds the generic >=0.01 BS1 threshold.	gnomad_v2 gnomad_v4
BS2	Not assessed	Not assessed: no healthy adult carrier or homozygote/hemizygote observation is documented, and penetrance and age-of-onset requirements cannot be established.	gnomad_v2 gnomad_v4
BS3	Not met	Not met: exact-variant assays showed impaired GTPase activity and abnormal signaling rather than no damaging effect on RHOA function or splicing.	PMID:24413734 PMID:24584070
BS4	Not assessed	Not assessed: no affected relatives with variant testing were documented, so non-segregation, phenocopies, and multiple familial variants cannot be evaluated.
BP1	Not assessed	Not assessed: the available RHOA evidence does not establish a disease spectrum caused primarily by truncating variants.	PMID:24413734 PMID:24584070
BP2	Not assessed	Not assessed: somatic lymphoma reports provide no fully penetrant dominant context or validated cis/trans relationship with a pathogenic variant.	clinvar PMID:24413734 PMID:24584070
BP3	N/A	Not applicable: BP3 requires an in-frame indel in a repeat region, and this is a missense variant.	pvs1_generic_framework generic_acmg_combination_rules
BP4	Not met	Not met: REVEL 0.952 exceeds the most permissive generic BP4 supporting threshold of <=0.29 for missense variants.	revel
BP5	Not met	Not met: TET2 co-mutations are reported, but no case demonstrates that an alternate molecular basis independently explains the disease.	PMID:24413737 PMID:24413734 PMID:24584070
BP6	Not met	Not met: no exact-variant ClinVar expert-panel Benign or Likely benign assertion is present; available submissions are non-expert Pathogenic or Oncogenic.	clinvar
BP7	N/A	Not applicable: BP7 requires a synonymous variant, and this is a missense variant.	generic_acmg_combination_rules

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