Variant classification summary

NM_002528.7:c.244C>T

NTHL1 · NP_002519.2:p.(Gln82Ter) · NM_002528.7

GRCh37: chr16:2096239 G>A · GRCh38: chr16:2046238 G>A

Gene: NTHL1 Transcript: NM_002528.7

Final call

Pathogenic

PVS1 very strong PS4 strong PM3 moderate PS3 supporting PP1 supporting

Variant details

Gene

NTHL1

Transcript

NM_002528.7

Protein

NP_002519.2:p.(Gln82Ter)

gnomAD AF

0.0015918670964542524 (v4.1)

ClinVar

Pathogenic

OncoKB

Classification rationale

Interpretation summary

Generated evidence synthesis

1

Pathogenic: PVS1 (very strong) is met because the NMD-competent nonsense p.(Gln82Ter) removes 73% of NTHL1 in a gene where biallelic loss of function causes disease.

2

Pathogenic: PS4 (strong) is met by variant-specific case-control enrichment in homozygous carriers (FinnGen OR 44.7, 95% CI 6.90-290).

3

Pathogenic: PM3 (moderate) is met because the allele occurs in trans with a likely pathogenic NTHL1 variant and homozygously in recessive polyposis patients.

4

Pathogenic: PS3 (supporting) is met because a variant-specific B-lymphocyte assay shows nonsense-mediated decay with about ten-fold reduced NTHL1 RNA.

5

Pathogenic: PP1 (supporting) is met because the equivalent allele co-segregated with adenomatous polyposis in three recessive families.

Final determination: Under the generic ACMG/AMP 2015 combination rules, one Very Strong pathogenic criterion (PVS1) plus one Strong pathogenic criterion (PS4) is sufficient for a Pathogenic classification.

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	Met at very strong: NMD-competent nonsense p.(Gln82Ter) removes the terminal 224 of 305 residues (73%), in a gene where biallelic loss of function causes disease.	pvs1_generic_framework pvs1_gene_context PMID:37727376 PMID:25741868
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.244C>T in NTHL1 is a nonsense substitution introducing a premature stop codon predicted to produce NP_002519.2:p.(Gln82Ter). 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 met	Not met: no proband, trio, or confirmed parental testing exists, and the same allele is documented as recessively inherited rather than de novo.	PMID:25938944 PMID:37727376 clinvar
PS3	Met	Met at supporting: a variant-specific B-lymphocyte qRT-PCR NMD assay in carriers shows this truncating allele undergoes nonsense-mediated decay with about ten-fold reduced NTHL1 RNA.	PMID:25938944 PMID:37727376 PMID:25741868 clinvar
PS4	Met	Met: variant-specific case-control enrichment in FinnGen, homozygous odds ratio 44.7 (95% CI 6.90-290, P=6.7e-5) versus the PS4 requirement of significantly increased prevalence in affecteds.	PMID:38036545 PMID:37727376
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.244C>T in NTHL1 is a nonsense substitution introducing a premature stop codon predicted to produce NP_002519.2:p.(Gln82Ter). 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 AF 0.00159 (2568/1613200 alleles), about 16-fold above the 0.0001 PM2 supporting threshold.	gnomad_v2 gnomad_v4 PMID:25741868
PM3	Met	Met: c.244C>T occurs in trans with a likely-pathogenic NTHL1 deletion and homozygously in multiple autosomal-recessive polyposis families.	PMID:37727376 PMID:25938944 clinvar
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.244C>T in NTHL1 is a nonsense substitution introducing a premature stop codon predicted to produce NP_002519.2:p.(Gln82Ter). 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.244C>T in NTHL1 is a nonsense substitution introducing a premature stop codon predicted to produce NP_002519.2:p.(Gln82Ter). 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 met	Not met: no proband or assumed de novo occurrence is reported, and the allele is documented as inherited from heterozygous carrier parents.	PMID:25938944 PMID:37727376
PP1	Met	Met at supporting: the equivalent truncating allele was homozygous in 7 affected members of 3 recessive NTHL1 families, with an unaffected heterozygous carrier.	PMID:25938944 PMID:37727376
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.244C>T in NTHL1 is a nonsense substitution introducing a premature stop codon predicted to produce NP_002519.2:p.(Gln82Ter). 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.244C>T is a nonsense (p.Gln82Ter) truncating variant, outside the missense/splice-region scope of PP3.
PP4	Not assessed	Not assessed: no proband phenotype or family history is recorded for this variant-only case, so the patient-specific phenotype PP4 requires cannot be evaluated.
PP5	Not met	Not met: ClinVar VCV000192319 has zero expert-panel submissions (review status 'criteria provided, single submitter', 1 star), so no expert-panel classification exists to trigger PP5.	clinvar
BA1	Not met	Not met: highest population AF 0.00463 (European Finnish) versus the 0.05 stand-alone BA1 threshold.	gnomad_v2 gnomad_v4 PMID:25741868
BS1	Not met	Not met: gnomAD AF 0.00159 (v4.1), highest Finnish subpopulation AF 0.00463, all below the 0.01 BS1 threshold.	gnomad_v2 gnomad_v4
BS2	Not met	Not met: one gnomAD homozygote exists, but NTHL1 tumor syndrome is adult-onset and incompletely penetrant, not the early-onset fully penetrant disorder BS2 requires.	gnomad_v2 gnomad_v4 PMID:37727376
BS3	Not met	Not met: the only variant-specific functional assay shows NTHL1 transcript loss via nonsense-mediated decay, a damaging effect rather than the normal function BS3 requires.	PMID:25938944 PMID:31285513 clinvar
BS4	Not met	Not met: no non-segregation is reported; the equivalent allele was homozygous in affected members of 3 families and heterozygous in an unaffected carrier.	PMID:25938944 PMID:37727376
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.244C>T in NTHL1 is a nonsense substitution introducing a premature stop codon predicted to produce NP_002519.2:p.(Gln82Ter). 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: the variant is biallelic (in trans) in autosomal-recessive NTHL1 disease, not in cis with a pathogenic variant.	PMID:37727376 PMID:25938944
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.244C>T in NTHL1 is a nonsense substitution introducing a premature stop codon predicted to produce NP_002519.2:p.(Gln82Ter). 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.244C>T is a nonsense (p.Gln82Ter) truncating variant, outside the missense/splice-region scope of BP4.
BP5	Not assessed	Not assessed: no proband genotype, co-occurring variant, or molecular diagnosis is available, so an alternate molecular basis for disease cannot be demonstrated.
BP6	Not met	Not met: ClinVar VCV000192319 has zero expert-panel submissions and no Benign/Likely benign assertion, so the BP6 expert-panel trigger is absent.	clinvar
BP7	N/A	BP7 (Richards et al. 2015, PMID:25741868) is defined for a synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence and the nucleotide is not highly conserved. NM_002528.7:c.244C>T in NTHL1 is a nonsense substitution introducing a premature stop codon predicted to produce NP_002519.2:p.(Gln82Ter). As a result, the encoded protein sequence is altered, so the criterion's silent-variant premise does not hold regardless of any splicing prediction, so BP7'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

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