NM_000314.8:c.253+5G>A

PTEN · NP_000305.3:p.? · NM_000314.8

GRCh37: chr10:89690851 G>A · GRCh38: chr10:87931094 G>A

Gene: PTEN Transcript: NM_000314.8

Final call

Likely Pathogenic

PVS1 PM2_Supporting

Variant details

Gene

PTEN

Transcript

NM_000314.8

Protein

NP_000305.3:p.?

gnomAD AF

ClinVar

OncoKB

Classification rationale

Interpretation summary

Generated evidence synthesis

An RNA study has shown that NM_000314.8:c.253+5G>A causes exon 4 skipping, resulting in the predicted frameshift transcript consequence p.(Ala72Thrfs*5).

Under the PTEN-specific PVS1 decision tree, a splice alteration that disrupts the reading frame in biologically relevant transcript NM_000314.8 and lies 5′ to p.D375 (c.1121) meets PVS1 at very strong strength; exon 4 skipping to p.(Ala72Thrfs*5) is consistent with this rule.

The variant is absent from gnomAD v2.1 and is observed at 0/1,448,024 alleles in gnomAD v4.1, with 0/33,128 alleles in the highest observed subpopulation, which is below the PTEN PM2 thresholds of 0.001% overall and 0.002% within any subpopulation and supports PM2_Supporting.

With PVS1 and PM2_Supporting under the PTEN VCEP framework, NM_000314.8:c.253+5G>A is classified as likely pathogenic.

Final determination:

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	Met	PMID:28677221 reports that NM_000314.8:c.253+5G>A causes exon 4 skipping with predicted protein consequence p.(Ala72Thrfs*5). Under the PTEN-specific PVS1 decision tree, a splice alteration that disrupts the reading frame and is predicted to undergo nonsense-mediated decay in biologically relevant transcript NM_000314.8, and that occurs 5' to p.D375 (c.1121), meets PVS1.	PMID:28677221 vcep_p_v_s_1___d_e_c_i_s_i_o_n_t_r_e_e___p_t_e_n
PS1	Not assessed	No same-nucleotide pathogenic splice comparator with equal or greater predicted impact was documented in the reviewed workspace materials.
PS2	Not assessed	No confirmed de novo data were provided.
PS3	Not assessed	An RNA study documents abnormal splicing, but this evidence was used to support PVS1 via the PTEN splice/null decision framework rather than being double-counted separately as PS3.	PMID:28677221 vcep_p_v_s_1___d_e_c_i_s_i_o_n_t_r_e_e___p_t_e_n
PS4	Not assessed	The reviewed materials did not provide PTEN phenotype specificity scoring or a case-control enrichment dataset sufficient for PS4.
PM1	Not met	This is an intronic splice-region variant, not a missense change within PTEN catalytic motif residues 90-94, 123-130, or 166-168.	cspec
PM2	Met	The variant is absent from gnomAD v2.1 and has 0/1,448,024 alleles in gnomAD v4.1, with 0/33,128 alleles in the highest observed subpopulation, which is below the PTEN PM2 thresholds of <0.001% overall and <0.002% within any subpopulation.	gnomad_v2 gnomad_v4 cspec
PM3	N/A	PM3 is not applicable for the PTEN VCEP framework.	cspec
PM4	Not met	This variant does not create an in-frame protein length change or stop-loss event.
PM5	Not met	This is not a missense variant at a residue with a different established pathogenic missense change.
PM6	Not assessed	No assumed de novo evidence was provided.
PP1	Not assessed	No segregation data were provided.
PP2	Not met	PP2 is a missense-specific rule and does not apply to this intronic splice-region variant.	cspec
PP3	Not assessed	SpliceAI shows a maximum delta score of 0.81, consistent with possible splice impact, but the PTEN VCEP rule for splicing variants requires concordance between SpliceAI and VarSeak, and no VarSeak result was available in the reviewed materials.	spliceai cspec
PP4	N/A	PP4 is not applicable for the PTEN VCEP framework because phenotype specificity is incorporated into PS4.	cspec
PP5	N/A	PP5 is not applicable for the PTEN VCEP framework.	cspec
BA1	Not met	The gnomAD v4.1 allele frequency is 0.0, which is well below the PTEN BA1 threshold of >0.056%.	gnomad_v4 cspec
BS1	Not met	The gnomAD v4.1 allele frequency is 0.0, which is below both the PTEN BS1 supporting range of 0.00043%-0.0043% and the strong range of 0.0043%-0.056%.	gnomad_v4 cspec
BS2	Not assessed	No homozygous observations in healthy or PTEN hamartoma tumor syndrome-unaffected individuals were provided.	gnomad_v4 cspec
BS3	Not assessed	No functional study demonstrating no damaging effect on splicing or PTEN function was provided.
BS4	Not assessed	No lack-of-segregation evidence was provided.
BP1	N/A	BP1 is not applicable for the PTEN VCEP framework.	cspec
BP2	Not assessed	No trans, cis, or phase-unknown observations with pathogenic PTEN variants were provided.
BP3	N/A	BP3 is not applicable for the PTEN VCEP framework.	cspec
BP4	Not met	SpliceAI predicts possible splice impact with a maximum delta score of 0.81, which is above the PTEN benign SpliceAI range of 0-0.2 required for BP4, and no concordant benign VarSeak result was provided.	spliceai cspec
BP5	Not assessed	No alternate highly penetrant molecular diagnosis with non-overlapping phenotype was provided.
BP6	N/A	BP6 is not applicable for the PTEN VCEP framework.	cspec
BP7	Not met	The variant is at +5, which is inside the PTEN BP7 positional requirement of at or beyond +7/-21, and SpliceAI predicts splice impact rather than no impact.	spliceai cspec

Disclaimer: The content and results provided by LYFE Sciences are for research and educational purposes only and must not be used as a substitute for professional medical judgment, diagnosis, or treatment. Always consult a qualified healthcare professional before making any clinical decisions.