Variant classification summary

NM_000367.5:c.719A>G

TPMT · NP_000358.1:p.(Tyr240Cys) · NM_000367.5

GRCh37: chr6:18130918 T>C · GRCh38: chr6:18130687 T>C

Gene: TPMT Transcript: NM_000367.5

Final call

Benign

PS3 supporting PP3 supporting BA1 stand-alone benign

Variant details

Gene

TPMT

Transcript

NM_000367.5

Protein

NP_000358.1:p.(Tyr240Cys)

gnomAD AF

0.042818153345960536 (v4.1)

ClinVar

Likely benign

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

Supporting evidence: TPMT*3C/A719G carriers showed intermediate enzymatic activity.

2

Supporting evidence: REVEL 0.703 exceeds the adjudicated missense threshold of 0.644.

3

Benign: gnomAD v4.1 grpmax FAF is 5.374767%, exceeding the 5% BA1 threshold.

Final determination: Under the generic ACMG/AMP 2015 fallback, BA1 alone is sufficient for a Benign call; the supporting PS3 and PP3 criteria do not meet any pathogenic combination rule.

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 met	Not met: the exact p.Tyr240Cys variant is reported as likely benign, with no independently established pathogenic same-amino-acid comparator identified.	clinvar PMID:9931346
PS2	Not assessed	Not assessed: no documented affected proband with confirmed maternity and paternity testing is available for this variant.
PS3	Met	Met at supporting strength: TPMT*3C/A719G carriers showed intermediate activity, with median 7.8 U/ml in African-Americans and 7.0 U/ml in the Caucasian carrier.	PMID:9931346
PS4	Not met	Not met: no affected-versus-control counts, odds ratio, or confidence interval establish the required PS4 enrichment for TPMT c.719A>G.	PMID:15819814 PMID:9931346
PM1	Not met	Not met: gnomAD v4.1 reports AF 0.0428182 and 1,714 homozygotes, demonstrating abundant benign population variation inconsistent with PM1.	gnomad_v4 hotspots
PM2	Not met	Not met: gnomAD v4.1 total AF is 4.281815%, far above the PM2 <=0.01% threshold, with 1,714 homozygotes.	gnomad_v4 gnomad_v2 PMID:25741868
PM3	Not assessed	Not assessed: no affected-proband observation or parental/offspring testing establishes c.719A>G in trans with a pathogenic variant.	PMID:9931346 PMID:25741868
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: no verified different pathogenic missense variant at Tyr240 is available to satisfy the same-residue PM5 requirement.	pm5_candidates
PM6	Not assessed	Not assessed: no assumed-de-novo observation without parental confirmation is documented for this variant.
PP1	Not assessed	Not assessed: zero informative affected-family meioses or variant-specific co-segregation results are documented.
PP2	Not assessed	Not assessed: no gene-wide evidence quantifies low benign missense variation and a common TPMT missense disease mechanism, the two PP2 prerequisites.	gnomad_v4 PMID:9931346
PP3	Met	Met at supporting: REVEL 0.703 exceeds the generic PP3 supporting threshold of >=0.644 for missense variants.	revel
PP4	Not assessed	Not assessed: no highly specific disease phenotype or family-history evidence is documented for TPMT c.719A>G.	PMID:15819814 PMID:9931346
PP5	Not met	Not met: no exact-variant expert-panel or qualifying reputable-source pathogenic assertion is available for TPMT c.719A>G.	clinvar
BA1	Met	Met: gnomAD v4.1 grpmax FAF is 5.374767%, exceeding the 5% BA1 threshold with 4,132 observed alleles in the contributing population.	gnomad_v4 gnomad_v2 clinvar PMID:9931346 PMID:25741868
BS1	Not assessed	Not assessed: grpmax FAF is 5.25% to 5.37%, but no disorder prevalence, penetrance, or allelic-heterogeneity inputs support a maximum-credible-frequency calculation.	gnomad_v4 gnomad_v2
BS2	Not assessed	Not assessed: gnomAD reports 1,714 homozygotes, but healthy-adult phenotype verification and early-age full penetrance are not established.	gnomad_v4 gnomad_v2 PMID:30447069
BS3	Not assessed	Not assessed: no variant-specific assay demonstrated normal TPMT function or splicing for c.719A>G; available data instead showed intermediate enzymatic activity.
BS4	Not assessed	Not assessed: no affected relative negative for the variant or documented non-segregating meiosis is available.
BP1	Not assessed	Not assessed: TPMT loss-of-function evidence is available, but the record does not establish a primarily truncating disease-variant spectrum.	PMID:30447069 PMID:9931346
BP2	Not assessed	Not assessed: no phase-resolved observation shows c.719A>G in trans or cis with a pathogenic variant under the BP2 rule.	PMID:9931346 PMID:25741868
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 0.703 is above the generic BP4 supporting cutoff of <=0.29 for missense variants.	revel
BP5	Not assessed	Not assessed: no case demonstrates an alternate molecular basis for disease alongside TPMT c.719A>G.	PMID:15819814 PMID:9931346
BP6	Not met	Not met: ClinVar has only non-expert laboratory Likely benign submissions and zero expert-panel submissions for this exact variant.	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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