LYFE Sciences · Project HERA
Variant Interpretation · Classification Report
Generated: 2026-08-26
Case ID: NM_007375.4_c.881G_T_20260826_110307
Framework: ACMG/AMP 2015
Variant classification summary

NM_007375.4:c.881G>T

TARDBP  · NP_031401.1:p.(Gly294Val)  · NM_007375.4
GRCh37: chr1:11082347 G>T  ·  GRCh38: chr1:11022290 G>T
Gene: TARDBP Transcript: NM_007375.4
Final call
VUS
PS3 supporting PM1 supporting PM2 supporting PP1 supporting PP2 supporting BP4 supporting
All criteria require review: For research and educational purposes only.
Variant details
Gene
TARDBP
Transcript
NM_007375.4
Protein
NP_031401.1:p.(Gly294Val)
gnomAD AF
3.0981583307618617e-06 (v4.1)
ClinVar
Pathogenic
OncoKB
Classification rationale
Interpretation summary
Generated evidence synthesis
1
PS3 (Supporting): two independent functional studies demonstrate abnormal variant biology.
2
PM1 (Supporting): variant disrupts the C-terminal glycine-rich domain where TARDBP disease variants cluster.
3
PM2 (Supporting): essentially absent from population databases (gnomAD v4.1 AF 3.1e-06, zero homozygotes).
4
PP1 (Supporting): cosegregation with ALS in an affected proband and sibling.
5
PP2 (Supporting): missense is the established TARDBP disease mechanism, with low benign tolerance in this domain.
6
BP4 (Supporting): SpliceAI predicts no splice impact (max delta 0.00).
7
Overall: VUS — five supporting pathogenic criteria against one supporting benign criterion meet no combination threshold under generic ACMG/AMP 2015.
Final determination: 5 supporting-only pathogenic criteria offset by 1 supporting benign criterion meets no generic ACMG combination threshold → 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: this is a missense change, so the loss-of-function rule for null variants does not apply.
pvs1_generic_framework generic_acmg_combination_rules
PS1 N/A Not applicable: no independent nucleotide change producing the same p.(Gly294Val) protein change was identified.
PS2 Not assessed Not assessed: no confirmed de novo occurrence with both biological parents tested was documented.
PS3 Met Met (Supporting): two independent functional studies show abnormal variant biology — accelerated amyloid formation with ~25% reduced cell viability, and neurodegeneration in patient-derived motor neurons.
PMID:25090004 PMID:29630989
PS4 Not assessed Not assessed: reported ALS cases may overlap and lack matched controls, so population enrichment could not be established.
final_classification_framework PMID:19224587 PMID:19236453 PMID:19864664 PMID:21651514 PMID:31852254
PM1 Met Met (Supporting): residue 294 lies in the C-terminal glycine-rich domain where essentially all disease-causing TARDBP missense variants cluster, and the change disrupts this domain.
PMID:19864664 PMID:19236453 PMID:19224587
PM2 Met Met (Supporting): essentially absent from population databases — gnomAD v4.1 allele frequency 3.1e-06 with zero homozygotes.
gnomad_v4 gnomad_v2 gnomad_canada PMID:31852254 PMID:19224587 PMID:19236453 PMID:19864664
PM3 N/A Not applicable: TARDBP ALS is autosomal-dominant, so the recessive-disease rule does not apply.
PMID:31852254 PMID:21651514
PM4 N/A Not applicable: the missense change does not alter protein length, which this rule requires.
pvs1_generic_framework generic_acmg_combination_rules
PM5 Not assessed Not assessed: no alternate amino-acid substitution at codon 294 with established pathogenicity was identified.
PM6 Not assessed Not assessed: parental genotyping was not documented, so a de novo occurrence could not be presumed.
PP1 Met Met (Supporting): the variant cosegregated with ALS in an affected proband and an affected sibling in a familial case.
PMID:19224587
PP2 Met Met (Supporting): TARDBP ALS/FTD is a missense-predominant disease gene, and the affected domain is absent from hundreds of control chromosomes.
PMID:19864664 PMID:19236453 PMID:19224587 PMID:25090004 PMID:29630989
PP3 Not met Not met: REVEL score 0.534 falls below the 0.644 supporting threshold, and SpliceAI predicts no splice impact.
revel bayesdel spliceai
PP4 Not assessed Not assessed: the evaluated individual's phenotype was not available for assessment.
final_classification_framework PMID:19236453 PMID:21651514 PMID:31852254
PP5 Not met Not met: no expert-panel ClinVar assertion of pathogenicity exists for this exact variant.
clinvar
BA1 Not met Not met: population frequency 3.1e-06 is far below the >1% benign threshold.
gnomad_v4 gnomad_v2
BS1 Not met Not met: the highest population frequency (~3.2e-05) is far below the >0.3% benign threshold.
gnomad_v4 gnomad_v2
BS2 Not assessed Not assessed: population data lack the phenotype, age, and penetrance information needed to establish benign homozygosity.
gnomad_v4 gnomad_v2 PMID:31852254
BS3 Not met Not met: the only functional studies show abnormal, not wild-type-like, behavior of the variant.
PMID:25090004 PMID:29630989
BS4 Not assessed Not assessed: relatives' genotypes and ages were not documented, so non-segregation could not be shown.
PMID:31852254
BP1 Not met Not met: TARDBP disease is driven by missense rather than truncating variants, the opposite of this rule's premise.
PMID:19864664 PMID:19236453
BP2 Not assessed Not assessed: no second pathogenic allele in trans or in cis with the variant was documented.
PMID:31852254 PMID:19864664 PMID:19224587
BP3 N/A Not applicable: this rule applies to in-frame insertions/deletions in repeat regions, not missense changes.
pvs1_generic_framework generic_acmg_combination_rules
BP4 Met Met (Supporting): SpliceAI predicts no splice impact (max delta 0.00), far below any splice-altering threshold.
spliceai revel bayesdel
BP5 Not assessed Not assessed: no alternate molecular diagnosis fully explaining the phenotype was documented.
BP6 Not met Not met: no expert-panel ClinVar assertion of benign effect exists for this exact variant.
clinvar
BP7 N/A Not applicable: this rule applies to synonymous (silent) variants, not missense changes.
generic_acmg_combination_rules
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