LYFE Sciences · Project HERA
Variant Interpretation · Classification Report
Generated: 2026-10-28
Case ID: NM_002528.7_c.503T_C_20261028_020430
Framework: ACMG/AMP 2015
Variant classification summary

NM_002528.7:c.503T>C

NTHL1  · NP_002519.2:p.(Ile168Thr)  · NM_002528.7
GRCh37: chr16:2094653 A>G  ·  GRCh38: chr16:2044652 A>G
Gene: NTHL1 Transcript: NM_002528.7
Final call
VUS
PP3 moderate BP1 supporting
All criteria require review: For research and educational purposes only.
Variant details
Gene
NTHL1
Transcript
NM_002528.7
Protein
NP_002519.2:p.(Ile168Thr)
gnomAD AF
0.0018092911360283416 (v4.1)
ClinVar
Likely benign
OncoKB
Classification rationale
Interpretation summary
Generated evidence synthesis
1
PP3 moderate: REVEL 0.876 supports a deleterious computational effect.
2
BP1 supporting: NTHL1 disease is primarily associated with biallelic inactivating and truncating alleles.
3
VUS: the PP3/BP1 combination meets no generic ACMG/AMP final-classification threshold.
Final determination: Under the generic ACMG/AMP 2015 fallback, PP3 moderate plus BP1 supporting satisfies neither a pathogenic nor a benign combination rule, resulting in VUS.
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: no previously established pathogenic NTHL1 variant producing p.Ile168Thr was identified in the reviewed evidence.
PMID:25741868 PMID:31068090 PMID:31285513 PMID:31227763
PS2 Not assessed Not assessed: no proband phenotype, family-history, or confirmed maternity-and-paternity results establish a de novo occurrence.
PS3 Not assessed Not assessed: no variant-specific validated functional assay was reported for NTHL1 c.503T>C (p.I168T).
PMID:31243857 PMID:31285513 PMID:31227763 PMID:31068090
PS4 Not assessed Not assessed: no exact-variant case-control odds ratio or confidence interval was available to compare with the PS4 >5.0 and CI-not-including-1.0 rule.
PMID:31227763 PMID:31243857 PMID:31285513
PM1 Not met Not met: residue 168 has no supplied authoritative domain assignment or statistically significant hotspot evidence.
PMID:25741868
PM2 Not met Not met: the default gnomAD v4.1 allele frequency is 0.0018092911, exceeding the <=0.0001 PM2 threshold.
gnomad_v2 gnomad_v4 PMID:25741868
PM3 Not assessed Not assessed: no affected-proband observation or parental testing establishes c.503T>C in trans with a pathogenic NTHL1 variant.
clinvar gnomad_v4 PMID:31227763 PMID:31243857 PMID:31068090 PMID:31285513
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 met Not met: no different missense variant at Ile168 with an established pathogenic determination was identified.
PMID:25741868 PMID:31068090 PMID:31285513 PMID:31227763
PM6 Not assessed Not assessed: no affected-patient de novo observation or parental testing supports an assumed de novo event without confirmed maternity and paternity.
PP1 Not assessed Not assessed: no affected relatives, informative meioses, or exact-variant genotype-phenotype segregation data are available.
PP2 Not met Not met: NTHL1 disease is described as biallelic inactivating, without evidence that missense variants commonly cause disease and benign missense variation is low.
PMID:25741868 PMID:31285513 PMID:31243857 PMID:31068090
PP3 Met Met at moderate strength: the missense variant's REVEL score is 0.876, exceeding the generic PP3 moderate threshold of 0.773.
revel generic_acmg_combination_rules PMID:25741868
PP4 Not assessed Not assessed: no patient phenotype or family history was available to establish specificity for a single-gene NTHL1-related disease.
PMID:31227763 PMID:31285513
PP5 Not assessed Not assessed: ClinVar had zero exact-variant expert-panel submissions and no reputable exact-variant pathogenic report meeting the PP5 trigger.
clinvar
BA1 Not met Not met: the highest observed population allele frequency is 0.0086148649, below the >=0.05 BA1 threshold.
gnomad_v2 gnomad_v4 PMID:25741868
BS1 Not met Not met: the highest observed population allele frequency is 0.0086148649, below the supplied >=0.01 BS1 threshold.
gnomad_v2 gnomad_v4 PMID:25741868
BS2 Not assessed Not assessed: gnomAD reports 9 homozygotes, but their healthy-adult status and age-appropriate disease penetrance are not documented.
gnomad_v2 gnomad_v4
BS3 Not assessed Not assessed: no variant-specific validated assay showed that NTHL1 c.503T>C (p.I168T) has no damaging effect on function or splicing.
PMID:31243857 PMID:31285513 PMID:31227763 PMID:31068090
BS4 Not assessed Not assessed: no phenotype-confirmed affected relatives with negative exact-variant testing are documented for evaluating lack of segregation.
BP1 Met Met at supporting strength: NTHL1 disease is described as biallelic inactivating, with recurrent truncating p.Gln90* alleles reported.
PMID:25741868 PMID:31285513 PMID:31243857 PMID:31068090 PMID:31227763
BP2 Not assessed Not assessed: no cis or trans phase observation with a pathogenic variant is documented for c.503T>C.
clinvar gnomad_v4 PMID:31227763 PMID:31243857 PMID:31068090 PMID:31285513
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: the missense variant's REVEL score is 0.876, well above the generic BP4 supporting cutoff of 0.29.
revel generic_acmg_combination_rules PMID:25741868
BP5 Not assessed Not assessed: no case-level alternate molecular diagnosis was documented alongside NM_002528.7:c.503T>C.
PMID:31068090 PMID:31227763 PMID:31285513
BP6 Not assessed Not assessed: ClinVar had zero exact-variant expert-panel submissions, so ordinary Likely benign laboratory assertions cannot trigger BP6.
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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