NM_000546.6:c.1100-3C>T

· ·

GRCh37: None · GRCh38: None

Gene: Transcript:

Final call

VUS

Variant details

Gene

Transcript

Protein

gnomAD AF

ClinVar

None

OncoKB

None

Classification rationale

Interpretation summary

Generated evidence synthesis

Under generic ACMG/AMP rules, PVS1 is not applicable because the submitted c.1100-3 substitution is outside the named canonical ±1/±2 splice-site and other null-variant classes; normalization and gene-level LOF context are unresolved.

PM4 and BP3 are not applicable because the submitted variant is an intronic single-nucleotide substitution, not an in-frame insertion/deletion or stop-loss variant.

All five requested criteria are not_assessed because the variant could not be normalized and the case evidence lacks the clinical, case-control, alternate-molecular-basis, and exact-variant ClinVar expert-panel data required for adjudication.

PP3 and BP4 are within scope only through the intronic SpliceAI path, but the variant could not be normalized and no SpliceAI score is available.

BP7 is outside scope because the submitted variant is intronic rather than synonymous.

All four population criteria are not assessed because the submitted intronic HGVS expression could not be normalized to a gene and genomic coordinate, leaving no usable population-frequency or healthy-adult observation data.

No criterion is inferred from another source's classification, and no VCEP-specific population rule applies because the case is governed by generic ACMG/AMP rules.

Final determination: Under the generic ACMG/AMP 2015 fallback, no applicable criteria were met, so none of the pathogenic, likely pathogenic, benign, or likely benign combination rules was satisfied and the result is 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
PVS1	N/A	Not applicable: the submitted intronic substitution is at position -3, outside PVS1's named canonical ±1 or ±2 splice-site locations and other null-variant classes.
PS1	N/A	Not applicable: c.1100-3C>T is intronic with no resolved amino acid change, so the same-amino-acid comparison required for PS1 cannot apply.
PS2	Not assessed	Not assessed: no documented proband, family-history status, or confirmed maternity and paternity is available to evaluate de novo occurrence.
PS3	Not assessed	Not assessed: no validated in vitro or in vivo functional assay evidence was available, and the variant could not be normalized for targeted evidence retrieval.
PS4	Not assessed	Not assessed: no case-control odds ratio or relative risk, confidence interval, or affected-versus-control prevalence data are available.
PM1	N/A	Not applicable: c.1100-3C>T has no resolved protein residue, so hotspot or critical-domain placement cannot be evaluated for this missense criterion.
PM2	Not assessed	Not assessed: no applicable population observation is available to test the <=0.0001 PM2 threshold or establish absence from controls.
PM3	Not assessed	Not assessed: no affected-proband observation, pathogenic allele, or parent/offspring phase testing establishes a PM3-relevant variant in trans.
PM4	N/A	Not applicable: the submitted variant is an intronic single-nucleotide substitution, not an in-frame insertion/deletion or stop-loss variant causing a protein-length change.
PM5	N/A	Not applicable: c.1100-3C>T is intronic with no resolved amino acid residue, so an alternate pathogenic missense change at the same residue cannot be assessed.
PM6	Not assessed	Not assessed: no proband de novo observation or parental testing status is documented for the variant.
PP1	Not assessed	Not assessed: no affected relatives, matching genotypes, phenotype data, or informative meioses are documented for segregation analysis.
PP2	N/A	Not applicable: c.1100-3C>T is intronic, not a missense variant, and has no resolved gene-level missense mechanism for PP2.
PP3	Not assessed	Not assessed: the applicable intronic SpliceAI path has no score, and transcript validation could not confirm the c.1100-3 location.
PP4	Not assessed	Not assessed: no patient phenotype or family history is provided to establish specificity for a single-gene disease.
PP5	Not assessed	Not assessed: no exact-variant ClinVar expert-panel Pathogenic or Likely pathogenic classification is available.
BA1	Not assessed	Not assessed: no population allele-frequency observation is available, so comparison with the >=0.05 BA1 threshold is impossible.
BS1	Not assessed	Not assessed: no observed population frequency is available for comparison with the generic BS1 threshold of >=0.01.
BS2	Not assessed	Not assessed: no healthy-adult homozygote, heterozygote, or hemizygote observation is available and penetrance is unresolved.
BS3	Not assessed	Not assessed: no validated in vitro or in vivo functional assay evidence was available, and the variant could not be normalized for targeted evidence retrieval.
BS4	Not assessed	Not assessed: no affected relatives with documented variant status and phenotype are available to evaluate lack of segregation.
BP1	N/A	Not applicable: c.1100-3C>T is intronic, not missense, and the gene was not resolved for evaluating a primarily truncating disease mechanism.
BP2	Not assessed	Not assessed: no resolved inheritance mode or documented cis/trans relationship with a pathogenic variant is available for BP2.
BP3	N/A	Not applicable: the submitted intronic single-nucleotide substitution is not an in-frame insertion or deletion, the required BP3 variant type.
BP4	Not assessed	Not assessed: the applicable intronic SpliceAI path has no score, and transcript validation could not confirm the c.1100-3 location.
BP5	Not assessed	Not assessed: no alternate molecular basis for the disease is documented in the available case evidence.
BP6	Not assessed	Not assessed: no exact-variant ClinVar expert-panel Benign or Likely benign classification is available.
BP7	N/A	Not applicable: c.1100-3C>T is an intronic-position change, whereas BP7 applies only to synonymous variants.

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