NM_014225.5:c.739A>G

PPP2R1A · NP_055040.2:p.(Thr247Ala) · NM_014225.5

GRCh37: chr19:52716295 A>G · GRCh38: chr19:52213042 A>G

Gene: PPP2R1A Transcript: NM_014225.5

Final call

VUS

PM2 supporting BP4 supporting

Variant details

Gene

PPP2R1A

Transcript

NM_014225.5

Protein

NP_055040.2:p.(Thr247Ala)

gnomAD AF

6.20784099981004e-07 (v4.1)

ClinVar

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

NM_014225.5:c.739A>G (p.Thr247Ala) is a missense variant in exon 6 of PPP2R1A, a gene associated with autosomal dominant Houge-Janssens syndrome type 2 (neurodevelopmental disorder). PVS1 is not applicable as this is a missense variant that does not fall into null-variant categories.

This variant is absent from gnomAD v2.1 and gnomAD-Canada, and is present at an extremely low frequency in gnomAD v4.1 (1/1,610,866 alleles; AF = 6.21 × 10⁻⁷), satisfying PM2 at supporting strength.

Multiple in silico predictors do not support a deleterious effect: REVEL score is 0.285 (below pathogenic threshold of 0.5), BayesDel score is −0.185 (predicted benign), and SpliceAI predicts no splicing impact (max delta = 0.00), satisfying BP4 at supporting strength.

No variant-specific functional studies, de novo reports, case-control data, segregation data, or ClinVar classifications exist for this variant. No pathogenic comparator variant at the same codon or residue has been identified. All remaining criteria are not met or not applicable.

The only applicable criteria are PM2_supporting and BP4_supporting, which carry equal and opposite weight. Under the generic ACMG/AMP 2015 combination rules (PMID:25741868), one supporting pathogenic criterion and one supporting benign criterion cancel each other, resulting in a classification of Variant of Uncertain Significance (VUS).

Final determination: Generic ACMG/AMP 2015 fallback rules do not meet benign, likely benign, likely pathogenic, or pathogenic combination thresholds, so the variant is classified as Variant of Uncertain Significance.

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	NM_014225.5:c.739A>G is a missense variant (p.Thr247Ala) and does not fall into the generic PVS1 null-variant buckets of nonsense, frameshift, or canonical ±1,2 splice consensus variants. Per ClinGen SVI PVS1 recommendations (PMC6185798), PVS1 is not applicable to this variant class.	pvs1_generic_framework
PS1	Not met	No same-amino-acid change (Thr247Ala or T247A) has been reported as pathogenic via a different nucleotide change in ClinVar or the literature. PS1 cannot be applied without an established pathogenic comparator at this position.	clinvar gnomad_v4
PS2	Not met	No de novo occurrence with confirmed parentage has been reported for NM_014225.5:c.739A>G. Literature search and ClinVar review did not identify any trio-based de novo observations for this variant.	clinvar
PS3	Not met	No variant-specific functional assays (e.g., PP2A phosphatase activity, substrate binding, or HEAT repeat structural integrity) have been performed for p.Thr247Ala. Well-established in vitro or in vivo functional studies supportive of a damaging effect are absent.
PS4	Not met	The variant is extremely rare (1/1,610,866 alleles in gnomAD v4.1). No case-control study demonstrates statistically enriched prevalence in affected individuals. The variant is absent from ClinVar, precluding affected case counts. Rarity in the general population does not independently satisfy PS4.	gnomad_v4 clinvar
PS5	Not met	No different missense change at the same codon (Thr247) has been established as pathogenic. PS5 requires a previously determined pathogenic variant at the same codon with a different amino acid substitution; no such comparator exists for codon 247.	clinvar
PM1	Not met	Residue Thr247 lies within HEAT repeat 6 of the PPP2R1A scaffold domain, a functionally important region for PP2A holoenzyme assembly. However, no statistical hotspot analysis (e.g., Cancer Hotspots) identifies position 247 as a recurrently mutated pathogenic site. Domain membership alone, without evidence of significant mutational clustering of pathogenic variants at this specific residue or immediate vicinity, is insufficient to meet PM1 under generic ACMG/AMP.	oncokb
PM2	Met	This variant is absent from gnomAD v2.1 and gnomAD-Canada v1.0, and present at an extremely low allele frequency in gnomAD v4.1 (1/1,610,866 alleles; AF = 6.21 × 10⁻⁷, 0.00006%), well below the 0.1% PM2 threshold for a rare variant absent from population databases. This constitutes PM2 at supporting strength.	gnomad_v2 gnomad_v4 gnomad_canada
PM5	Not met	No pathogenic missense variant at the same amino acid residue (Thr247) has been identified in ClinVar. Automated candidate harvesting found zero same-residue comparator variants. PM5 requires a different pathogenic missense change at the same position, which is not available.	clinvar pm5_candidates
PM6	Not met	No de novo observation (even without confirmed parentage) has been reported for NM_014225.5:c.739A>G. Literature and ClinVar searches did not identify any presumed de novo occurrence.	clinvar
PP1	Not met	No families with multiple affected individuals segregating this variant have been published. No co-segregation data are available.
PP2	Not met	While PPP2R1A is an autosomal dominant neurodevelopmental disorder gene in which missense variants are a known mechanism, PP2 additionally requires demonstration of a low rate of benign missense variation in the gene. REVEL (0.285) and BayesDel (-0.185) scores do not indicate strong constraint at this residue, and no gene-level missense constraint metric (e.g., missense Z-score above 3.09) has been provided. Under generic ACMG/AMP, PP2 is not met without this supporting constraint evidence.	revel bayesdel
PP3	Not met	Multiple in silico prediction tools do not support a deleterious effect. REVEL score is 0.285 (below commonly used pathogenic threshold of 0.5), BayesDel score is -0.184741 (negative, predicting benign), and SpliceAI predicts no splicing impact (max delta = 0.00). No in silico tool predicts a damaging effect.	revel bayesdel spliceai
PP4	Not met	No clinical phenotype information for the proband is available for assessment. PP4 requires that the patient's phenotype or family history is highly specific for a disease with a single genetic etiology, which cannot be evaluated without clinical data.
PP5	Not met	The variant is absent from ClinVar. PP5 requires a reputable source (e.g., clinical diagnostic laboratory) to have classified the variant as pathogenic, which is not available.	clinvar
BA1	Not met	The variant is not a common polymorphism. gnomAD v4.1 allele frequency is 6.21 × 10⁻⁷ (0.00006%), far below the 1% BA1 threshold. The variant is absent from gnomAD v2.1 and gnomAD-Canada.	gnomad_v2 gnomad_v4 gnomad_canada
BS1	Not met	The variant allele frequency in gnomAD v4.1 (6.21 × 10⁻⁷, 0.00006%) is far below the 0.3% BS1 threshold for a variant too common to cause a dominant fully penetrant disorder. The variant remains exceptionally rare.	gnomad_v2 gnomad_v4 gnomad_canada
BS2	Not met	No homozygous observation of this variant has been reported in any population database. The single heterozygous observation in gnomAD v4.1 does not constitute observation in a healthy adult homozygous state, which is required for BS2.	gnomad_v4
BS3	Not met	No well-established in vitro or in vivo functional studies demonstrate that p.Thr247Ala does not affect protein function. No functional assays specific to this variant have been performed.
BS4	Not met	No segregation data are available in affected families. BS4 requires lack of segregation with disease, which cannot be evaluated without family studies.
BP1	Not met	BP1 applies when a missense variant occurs in a gene for which only truncating variants cause disease. PPP2R1A-related neurodevelopmental disorder (Houge-Janssens syndrome type 2) is primarily caused by missense variants, not solely truncating variants. BP1 is not applicable to this gene-disease mechanism.
BP2	Not met	The variant has not been observed in trans with a known pathogenic PPP2R1A variant. PPP2R1A-associated neurodevelopmental disorder is autosomal dominant, making such an observation unlikely. No observation in cis with a pathogenic variant has been reported either.
BP4	Met	Multiple lines of computational evidence suggest no impact on the gene product. REVEL score is 0.285 (below commonly used pathogenic threshold of 0.5), BayesDel score is -0.184741 (negative, predicted benign), and SpliceAI predicts no splicing alteration (max delta = 0.00). All three in silico predictors are concordant in not supporting a deleterious effect.	revel bayesdel spliceai
BP5	Not met	BP5 requires a reputable source to have classified the variant as benign or to have found an alternative molecular basis for disease in a case. The variant is absent from ClinVar, and no such alternative molecular finding is documented.	clinvar
BP6	Not met	The variant is absent from ClinVar. BP6 requires a reputable source to classify the variant as benign, which is not available.	clinvar
BP7	N/A	BP7 applies specifically to synonymous (silent) variants for which splicing prediction algorithms predict no impact and the nucleotide is not highly conserved. NM_014225.5:c.739A>G is a missense variant (p.Thr247Ala), not a synonymous variant. BP7 is not applicable to missense variants per ACMG/AMP framework.
BP3	N/A	This variant is a substitution, not an in-frame insertion/deletion in a repetitive region. BP3 is trivially not applicable.
PM3	N/A	PPP2R1A-associated neurodevelopmental disorder is autosomal dominant. PM3 applies exclusively to recessive disorders (detected in trans with a pathogenic variant).
PM4	N/A	This variant is a substitution, not a protein-length-altering change (in-frame deletion/insertion, stop-loss, or initiation codon variant). PM4 is trivially not applicable.

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