Classification rationale

BP7 VUS

NTHL1 c.900C>T synonymous · exon 6

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.

BP7 → VUS

LYFE Sciences is an AI system, and it can make mistakes. Criteria may be applied incorrectly, sources may be misread, and a confident-looking classification can still be wrong. Double-check every criterion and its underlying evidence before relying on any call.

Gene diagram · NM_002528.7 · variants mapped to exon structure

NTHL1 NM_002528.7

Fetching transcript structure from UCSC…

Applied criteria · 1 applied · 17 assessed

MetEvidence satisfies this criterion.

Not metEvaluated against available evidence; threshold not reached.

Not assessedApplies in principle, but no evidence was found to evaluate it.

N/ADoesn't apply to this variant type.

Applied · 1

Strength Supporting Moderate Strong Very strong

BP7 supporting review Benign

Met at supporting: synonymous p.(Ala300=) with SpliceAI max delta 0.004, far below the 0.2 significant-splice-impact cutoff.

The variant is synonymous: NM_002528.7:c.900C>T, NP_002519.2:p.(Ala300=), exon 6 of NTHL1; BP7, not PP3/BP4, is the computational criterion in scope for it.SpliceAI scores for NM_002528.7:c.900C>T are DS_AG 0.003, DS_AL 0.004, DS_DG 0.002 and DS_DL 0.00, giving a maximum delta score of 0.004, with no predicted acceptor or donor gain or loss; the predicted event positions are DP_AL 123, DP_DL 188, DP_DG 194 and DP_AG 277 nucleotides from the variant.The SpliceAI recommended cutoff for significant splice impact is 0.2, with 0.1 as the no-impact level (Jaganathan et al. 2019, Cell, PMID:30661751); the observed maximum delta of 0.004 is far below both, satisfying BP7's no-predicted-splice-impact requirement.

spliceai ↗PMID:25741868 ↗gnomad_v2 ↗gnomad_v4 ↗

Assessed · not applied · 9 not met · 8 not assessed

Pathogenic

PS2 Not assessed: no proband, parental testing or family history data exist to establish a confirmed de novo occurrence.

PS3 Not assessed: no functional assay data exist for this synonymous p.(Ala300=) variant; only computational SpliceAI (max delta 0.004), which cannot support PS3.

PS4 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.

PM2 Not met: gnomAD v4.1 frequency 0.021% (341/1,603,718 alleles; 4 homozygotes) exceeds the 0.01% PM2 threshold.

PM3 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).

PM6 Not assessed: no de novo occurrence of c.900C>T is reported and no parental genotypes exist to assume one.

PP1 Not assessed: no pedigree or affected-relative genotypes exist, so co-segregation with disease cannot be evaluated.

PP4 Not assessed: no proband phenotype is documented; the only context is the non-specific ClinVar testing indication 'hereditary cancer-predisposing syndrome'.

PP5 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.

Benign

BA1 Not met: the highest population frequency (South Asian, 0.39%) is still far below the 5% stand-alone BA1 threshold.

BS1 Not met: the maximum population frequency, 0.39% in South Asians, is below the generic 1% BS1 threshold.

BS2 Not met: the 3-4 population homozygotes are not phenotype-documented healthy adults, and NTHL1 tumor syndrome is not early-onset and fully penetrant.

BS3 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.

BS4 Not assessed: no family with multiple affected members was genotyped, so lack of segregation cannot be evaluated.

BP2 Not met: no cis/trans phase observation with any pathogenic NTHL1 variant exists, and NTHL1 tumor syndrome is a recessive, not dominant, disorder.

BP5 Not assessed: no affected case carrying this variant is documented, so the alternate-molecular-basis observation BP5 requires is absent.

BP6 Not met: ClinVar VCV000757993 aggregate is 2-star Benign/Likely benign but has no expert-panel submission, and non-expert labels cannot trigger BP6.

N/A · 10 PVS1 · PS1 · PM1 · PM4 · PM5 · PP2 · PP3 · BP1 · BP3 · BP4

Research & evidence

Population frequency

gnomAD v4.1

gnomAD v2.1

v4.1

This variant is present in gnomAD v4.1 (AF= 0.000212631; MAF= 0.02126%, 341/1603718 alleles, homozygotes = 4) and has highest observed frequency in the South Asian population (AF= 0.0032941; MAF= 0.32941%, 300/91072 alleles, homozygotes = 4); grpmax FAF= 0.00298711.

v2.1

This variant is present in gnomAD v2.1 (AF= 0.000459157; MAF= 0.04592%, 125/272238 alleles, homozygotes = 3) and has highest observed frequency in the South Asian population (AF= 0.00389423; MAF= 0.38942%, 119/30558 alleles, homozygotes = 3); grpmax FAF= 0.00332598.

🇨🇦 CA

This variant is present in gnomAD-Canada v1.0 (AF= 0.00032590983161325367, 6/18410 alleles, homozygotes = 0).

Allele frequency by ancestry

three datasets · side by side

gnomAD v4.1

0.021% · 341 / 1,603,718
4 hom · FAF 0.3%

South Asian 300 / 91,072	0.33% 4 hom
Remaining individuals 19 / 62,418	0.03%
African/African American 2 / 75,048	0.0027%
Admixed American 1 / 60,016	0.0017%
European (non-Finnish) 19 / 1,179,866	0.0016%

+ 5 not observed (European (Finnish), Amish, East Asian, Middle Eastern, Ashkenazi Jewish)

gnomAD v2.1

0.046% · 125 / 272,238
3 hom · FAF 0.33%

South Asian 119 / 30,558	0.39% 3 hom
Remaining individuals 6 / 7,094	0.085%

+ 6 not observed (African/African American, Admixed American, Ashkenazi Jewish, East Asian, European (Finnish), European (non-Finnish))

gnomAD Canada 🇨🇦

0.033% · 6 / 18,410
0 hom · FAF 0.19%

South Asian

6 / 1,362

0.44%

+ 8 not observed (African/African American, Latino/Admixed American, Ashkenazi Jewish, East Asian, European (Finnish), Middle Eastern, European (non-Finnish), Remaining individuals)

gnomAD v4 ↗ gnomAD v2 ↗ gnomAD 🇨🇦 ↗

ClinVar

This variant has been reported in ClinVar as Likely benign (3 clinical laboratories) and as Benign (2 clinical laboratories). (ClinVarID = 757993)

ClinVar ↗

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00).

SpliceAI ↗

Functional Unknown Oncogenic Effect

OncoKB identified curated literature and non-variant-specific oncogenicity context for review; listed oncogenicity label: Unknown Oncogenic Effect.

OncoKB ↗

COSMIC

Cancer hotspots

Somatic evidence Not in COSMIC / hotspots

COSMIC

This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).

Hotspots

This variant does not lie in a statistically significant hotspot.

COSMIC ↗ Hotspots ↗

Literature · how each cited paper was used

1papers cited

Each card is an audit: what was searched, what was found, whether it names the variant, which criteria it fed, and why. 3 further PMIDs triaged but not cited — see Sources & references.

Rule & framework references · cited for criterion definitions, not variant evidence

25741868 ↗ Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Sources & reference links

8Sources

ClinVar

gnomAD v2.1

gnomAD v4.1

gnomAD-Canada

SpliceAI

OncoKB

COSMIC

Cancer hotspots

Triaged references · 3 PMIDs not cited in assessment

25394175 ↗ A practice guideline from the American College of Medical Genetics and Genomics and the National Society of Genetic Counselors: referral indications for cancer predisposition assessment. CLINVAR

32239880 ↗ NTHL1 Tumor Syndrome. CLINVAR

28492532 ↗ Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria. CLINVAR

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