Variant classification summary

NM_002528.7:c.900C>T

NTHL1 · NP_002519.2:p.(Ala300=) · NM_002528.7

GRCh37: chr16:2089940 G>A · GRCh38: chr16:2039939 G>A

Gene: NTHL1 Transcript: NM_002528.7

Final call

VUS

BP7 supporting

Variant details

Gene

NTHL1

Transcript

NM_002528.7

Protein

NP_002519.2:p.(Ala300=)

gnomAD AF

0.00021263089894856826 (v4.1)

ClinVar

Likely benign

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

BP7 (supporting): the synonymous p.(Ala300=) change has SpliceAI max delta 0.004, far below the 0.2 splice-impact cutoff, indicating no effect on splicing.

Final determination: Under the generic ACMG/AMP 2015 combining rules, a single supporting benign criterion (BP7) with no pathogenic criteria met satisfies neither the Likely Benign (1 strong + 1 supporting, or 2 supporting) nor any Pathogenic/Likely Pathogenic combination, giving 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	PVS1 (ClinGen SVI PVS1 recommendations, PMC6185798, pvs1_generic_framework) applies only to null variant classes — nonsense, frameshift, canonical ±1/2 splice-consensus, translation-initiation-codon loss, and stop-loss variants — each expected to trigger nonsense-mediated decay or otherwise abolish normal protein function. NM_002528.7:c.900C>T in NTHL1 is a synonymous (silent) substitution predicted to produce NP_002519.2:p.(Ala300=). As a result, no null-variant mechanism (nonsense-mediated decay, truncation, or canonical splice disruption) is triggered by this variant class, so PVS1's structural prerequisite is not met by this variant class. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication, because no structured VCEP criteria-combination framework governs this case (framework_complete=false); the generic ACMG/AMP 2015 fallback applies.	pvs1_generic_framework generic_acmg_combination_rules
PS1	N/A	PS1 (Richards et al. 2015, PMID:25741868) requires the same amino acid change as a previously established pathogenic variant, evaluated regardless of the underlying nucleotide change. NM_002528.7:c.900C>T in NTHL1 is a synonymous (silent) substitution predicted to produce NP_002519.2:p.(Ala300=). As a result, no altered amino acid exists at this position to compare against any previously established pathogenic missense variant, so PS1's structural prerequisite is not met by this variant class. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication, because no structured VCEP criteria-combination framework governs this case (framework_complete=false); the generic ACMG/AMP 2015 fallback applies.	generic_acmg_combination_rules
PS2	Not assessed	Not assessed: no proband, parental testing or family history data exist to establish a confirmed de novo occurrence.	PMID:25741868 generic_acmg_combination_rules final_classification_framework
PS3	Not assessed	Not assessed: no functional assay data exist for this synonymous p.(Ala300=) variant; only computational SpliceAI (max delta 0.004), which cannot support PS3.	spliceai clinvar oncokb PMID:25741868 PMID:25394175 PMID:28492532 PMID:32239880
PS4	Not met	Not met: no case-control enrichment exists; the variant sits in gnomAD population controls (v4.1 AF 0.0213%, 4 homozygotes) rather than enriched in affected individuals.	clinvar gnomad_v4 gnomad_v2 PMID:25394175 PMID:32239880
PM1	N/A	PM1 (Richards et al. 2015, PMID:25741868) applies to a missense variant located in a mutational hot spot and/or a critical, well-established functional domain without benign variation. NM_002528.7:c.900C>T in NTHL1 is a synonymous (silent) substitution predicted to produce NP_002519.2:p.(Ala300=). As a result, no altered residue exists to evaluate for mutational hot-spot or critical-domain membership, so PM1's structural prerequisite is not met by this variant class. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication, because no structured VCEP criteria-combination framework governs this case (framework_complete=false); the generic ACMG/AMP 2015 fallback applies.	generic_acmg_combination_rules
PM2	Not met	Not met: gnomAD v4.1 frequency 0.021% (341/1,603,718 alleles; 4 homozygotes) exceeds the 0.01% PM2 threshold.	gnomad_v2 gnomad_v4 PMID:25741868
PM3	Not met	Not met: no affected proband or phase-resolved observation places this variant in trans with a pathogenic NTHL1 allele, while gnomAD records 4 homozygotes (v4.1).	pvs1_gene_context clinvar gnomad_v2 gnomad_v4 PMID:25741868
PM4	N/A	PM4 (Richards et al. 2015, PMID:25741868) applies to protein length changes: in-frame insertions/deletions in a non-repetitive region, or stop-loss variants that extend the protein past the reference stop codon. NM_002528.7:c.900C>T in NTHL1 is a synonymous (silent) substitution predicted to produce NP_002519.2:p.(Ala300=). As a result, no change in protein length occurs, so there is nothing for this criterion to evaluate, so PM4's structural prerequisite is not met by this variant class. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication, because no structured VCEP criteria-combination framework governs this case (framework_complete=false); the generic ACMG/AMP 2015 fallback applies.	pvs1_generic_framework generic_acmg_combination_rules
PM5	N/A	PM5 (Richards et al. 2015, PMID:25741868) requires a novel missense change at an amino acid residue where a different missense change has previously been determined to be pathogenic. NM_002528.7:c.900C>T in NTHL1 is a synonymous (silent) substitution predicted to produce NP_002519.2:p.(Ala300=). As a result, no missense change exists at this residue to compare against a different pathogenic missense change at the same position, so PM5's structural prerequisite is not met by this variant class. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication, because no structured VCEP criteria-combination framework governs this case (framework_complete=false); the generic ACMG/AMP 2015 fallback applies.	generic_acmg_combination_rules
PM6	Not assessed	Not assessed: no de novo occurrence of c.900C>T is reported and no parental genotypes exist to assume one.	PMID:25741868 generic_acmg_combination_rules final_classification_framework
PP1	Not assessed	Not assessed: no pedigree or affected-relative genotypes exist, so co-segregation with disease cannot be evaluated.	PMID:25741868 generic_acmg_combination_rules final_classification_framework
PP2	N/A	PP2 (Richards et al. 2015, PMID:25741868) applies to a missense variant in a gene with a low rate of benign missense variation, where missense variants are a common mechanism of disease. NM_002528.7:c.900C>T in NTHL1 is a synonymous (silent) substitution predicted to produce NP_002519.2:p.(Ala300=). As a result, the gene's missense-constraint properties are irrelevant because no missense change is present to evaluate, so PP2's structural prerequisite is not met by this variant class. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication, because no structured VCEP criteria-combination framework governs this case (framework_complete=false); the generic ACMG/AMP 2015 fallback applies.	generic_acmg_combination_rules
PP3	N/A	Not applicable: c.900C>T is synonymous, p.(Ala300=), outside PP3's missense and intronic/splice-region scope.	generic_acmg_combination_rules pvs1_variant_assessment
PP4	Not assessed	Not assessed: no proband phenotype is documented; the only context is the non-specific ClinVar testing indication 'hereditary cancer-predisposing syndrome'.	clinvar
PP5	Not met	Not met: the exact ClinVar record VCV000757993 (NM_002528.7:c.900C>T) has zero expert-panel submissions, only six single-submitter laboratory records aggregated as 2-star Benign/Likely benign.	clinvar
BA1	Not met	Not met: the highest population frequency (South Asian, 0.39%) is still far below the 5% stand-alone BA1 threshold.	gnomad_v2 gnomad_v4 PMID:25741868
BS1	Not met	Not met: the maximum population frequency, 0.39% in South Asians, is below the generic 1% BS1 threshold.	gnomad_v2 gnomad_v4
BS2	Not met	Not met: the 3-4 population homozygotes are not phenotype-documented healthy adults, and NTHL1 tumor syndrome is not early-onset and fully penetrant.	gnomad_v2 gnomad_v4 PMID:25741868
BS3	Not assessed	Not assessed: no functional assay demonstrating absence of a damaging effect exists for this synonymous variant; computational SpliceAI max delta 0.004 is not assay evidence.	spliceai clinvar oncokb PMID:25741868 PMID:25394175 PMID:28492532 PMID:32239880
BS4	Not assessed	Not assessed: no family with multiple affected members was genotyped, so lack of segregation cannot be evaluated.	PMID:25741868 generic_acmg_combination_rules final_classification_framework
BP1	N/A	BP1 (Richards et al. 2015, PMID:25741868) applies to a missense variant in a gene for which primarily truncating variants are known to cause disease. NM_002528.7:c.900C>T in NTHL1 is a synonymous (silent) substitution predicted to produce NP_002519.2:p.(Ala300=). As a result, the gene's truncating-variant mechanism is irrelevant because no missense change is present to evaluate, so BP1's structural prerequisite is not met by this variant class. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication, because no structured VCEP criteria-combination framework governs this case (framework_complete=false); the generic ACMG/AMP 2015 fallback applies.	generic_acmg_combination_rules
BP2	Not met	Not met: no cis/trans phase observation with any pathogenic NTHL1 variant exists, and NTHL1 tumor syndrome is a recessive, not dominant, disorder.	PMID:25741868 pvs1_gene_context clinvar
BP3	N/A	BP3 (Richards et al. 2015, PMID:25741868) applies to in-frame insertions/deletions located in a repetitive region without a known function. NM_002528.7:c.900C>T in NTHL1 is a synonymous (silent) substitution predicted to produce NP_002519.2:p.(Ala300=). As a result, the variant does not alter protein length within a repeat region, so there is nothing for this criterion to evaluate, so BP3's structural prerequisite is not met by this variant class. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication, because no structured VCEP criteria-combination framework governs this case (framework_complete=false); the generic ACMG/AMP 2015 fallback applies.	pvs1_generic_framework generic_acmg_combination_rules
BP4	N/A	Not applicable: c.900C>T is synonymous, p.(Ala300=), so BP4's missense and intronic/splice-region paths are outside this variant's scope.	generic_acmg_combination_rules pvs1_variant_assessment
BP5	Not assessed	Not assessed: no affected case carrying this variant is documented, so the alternate-molecular-basis observation BP5 requires is absent.	clinvar PMID:25394175 PMID:32239880
BP6	Not met	Not met: ClinVar VCV000757993 aggregate is 2-star Benign/Likely benign but has no expert-panel submission, and non-expert labels cannot trigger BP6.	clinvar
BP7	Met	Met at supporting: synonymous p.(Ala300=) with SpliceAI max delta 0.004, far below the 0.2 significant-splice-impact cutoff.	spliceai PMID:25741868 gnomad_v2 gnomad_v4

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