Variant classification summary

NM_002528.7:c.31C>T

NTHL1 · NP_002519.2:p.(Arg11Trp) · NM_002528.7

GRCh37: chr16:2097794 G>A · GRCh38: chr16:2047793 G>A

Gene: NTHL1 Transcript: NM_002528.7

Final call

VUS

PM2 supporting BP4 supporting

Variant details

Gene

NTHL1

Transcript

NM_002528.7

Protein

NP_002519.2:p.(Arg11Trp)

gnomAD AF

5.2785171891141895e-05 (v4.1)

ClinVar

Uncertain significance

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

PM2 (Supporting): gnomAD v4.1 allele frequency 0.00528% overall (maximum 0.01472%), below the 0.1% rarity threshold.

2

BP4 (Supporting): REVEL score 0.196 falls below the 0.250 threshold, predicting a benign protein-level effect.

3

Overall classification: Uncertain Significance - one supporting pathogenic criterion (PM2) and one supporting benign criterion (BP4) satisfy no ACMG/AMP 2015 combination rule.

Final determination: Generic ACMG/AMP 2015 fallback: a single supporting pathogenic criterion (PM2) combined with a single supporting benign criterion (BP4), with no other met criteria, does not reach any Pathogenic, Likely Pathogenic, Benign, or Likely Benign combination threshold, so the variant is classified as 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	Not applicable: PVS1 applies only to null variants, and c.31C>T is a missense change (p.Arg11Trp) with no nonsense-mediated decay mechanism.	pvs1_generic_framework generic_acmg_combination_rules
PS1	Not assessed	Not assessed: no alternate codon producing p.Arg11Trp with an established pathogenic classification was identified.	clinvar
PS2	Not assessed	Not assessed: no parental genotypes, parentage confirmation, or de novo observations for p.Arg11Trp were available.
PS3	Not assessed	Not assessed: no functional assay results (e.g., glycosylase activity or DNA repair assays) for p.Arg11Trp were available.
PS4	Not assessed	Not assessed: no case-control counts, odds ratio, or affected-case series for p.Arg11Trp were available.
PM1	Not assessed	Not assessed: no NTHL1 domain-boundary or hotspot annotation was available, and CancerHotspots reported no significant hotspot at residue 11.
PM2	Met	Met (supporting): gnomAD v4.1 allele frequency 0.00528% overall (maximum 0.01472%), below the 0.1% PM2 rarity threshold.	gnomad_v2 gnomad_v4 PMID:25741868
PM3	Not assessed	Not assessed: no affected individual with p.Arg11Trp in trans with a pathogenic NTHL1 variant was reported.	PMID:25741868 PMID:33980861
PM4	N/A	Not applicable: PM4 applies to in-frame indels or stop-loss variants, and c.31C>T is a missense change with no protein-length alteration.	pvs1_generic_framework generic_acmg_combination_rules
PM5	Not assessed	Not assessed: no alternate missense change at Arg11 with an established pathogenic classification was identified.	pm5_candidates
PM6	Not assessed	Not assessed: no de novo occurrence with unconfirmed parental testing was reported.
PP1	Not assessed	Not assessed: no pedigree or affected-relative genotype data were available to evaluate co-segregation.
PP2	Not assessed	Not assessed: NTHL1 disease is driven by biallelic loss-of-function variants, and no missense-constraint metric was available to assess benign missense rate.	pvs1_gene_context
PP3	Not met	Not met: REVEL score 0.196 falls below the 0.250 BP4 threshold, not above the 0.750 PP3 threshold.	revel generic_acmg_combination_rules
PP4	Not assessed	Not assessed: no individual-level phenotype or tumor data were provided.
PP5	Not met	Not met: ClinVar holds only non-expert Uncertain significance submissions, with no expert-panel Pathogenic or Likely pathogenic assertion.	clinvar
BA1	Not met	Not met: highest population allele frequency is 0.01472% (gnomAD v4.1), far below the 1% BA1 threshold.	gnomad_v2 gnomad_v4 PMID:25741868
BS1	Not met	Not met: highest population allele frequency 0.01472% (gnomAD v4.1) is below the 0.3% BS1 threshold.	gnomad_v2 gnomad_v4 PMID:25741868
BS2	Not met	Not met: gnomAD v4.1 (84 alleles) and v2.1 (9 alleles) report zero homozygotes, so no benign homozygous observation is documented.	gnomad_v2 gnomad_v4 PMID:25741868
BS3	Not assessed	Not assessed: no functional assay results demonstrating normal (wild-type-like) activity for p.Arg11Trp were available.
BS4	Not assessed	Not assessed: no family data showing the variant failing to track with disease were available.
BP1	Not assessed	Not assessed: NTHL1 disease is loss-of-function driven, but no gene-specific statistic or VCEP rule establishes missense variants as benign.	pvs1_gene_context
BP2	Not assessed	Not assessed: no co-occurrence or phase data with a pathogenic variant were available, and gnomAD v4.1 (84 alleles) shows no homozygotes.	PMID:25741868 PMID:33980861 gnomad_v4
BP3	N/A	Not applicable: BP3 applies to in-frame indels in repetitive regions, and c.31C>T is a missense change.	pvs1_generic_framework generic_acmg_combination_rules
BP4	Met	Met (supporting): REVEL score 0.196 falls below the 0.250 BP4 threshold, predicting a benign protein-level effect.	revel generic_acmg_combination_rules
BP5	Not assessed	Not assessed: no affected individual, phenotype, or alternate molecular diagnosis was provided.
BP6	Not met	Not met: ClinVar holds only non-expert Uncertain significance submissions, with no expert-panel Benign or Likely benign assertion.	clinvar
BP7	N/A	Not applicable: BP7 applies to synonymous variants, and c.31C>T is a missense change that alters the encoded protein.	generic_acmg_combination_rules

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