LYFE Sciences · Project HERA
Variant Interpretation · Classification Report
Generated: 2026-08-26
Case ID: NM_007375.4_c.883G_A_20260826_111207
Framework: ACMG/AMP 2015
Variant classification summary

NM_007375.4:c.883G>A

TARDBP  · NP_031401.1:p.(Gly295Ser)  · NM_007375.4
GRCh37: chr1:11082349 G>A  ·  GRCh38: chr1:11022292 G>A
Gene: TARDBP Transcript: NM_007375.4
Final call
VUS
PM1 moderate PM2 moderate PP2 supporting
All criteria require review: For research and educational purposes only.
Variant details
Gene
TARDBP
Transcript
NM_007375.4
Protein
NP_031401.1:p.(Gly295Ser)
gnomAD AF
1.239192690745833e-06 (v4.1)
ClinVar
Pathogenic
OncoKB
Classification rationale
Interpretation summary
Generated evidence synthesis
1
PM1 (Moderate): Gly295 lies in the exon-6 glycine-rich C-terminal domain, an established mutational hotspot for TARDBP-related ALS/FTLD.
2
PM2 (Moderate): the variant is extremely rare - 2 of 1,613,954 gnomAD v4.1 alleles (AF 1.24e-06), below the 0.1% population threshold.
3
PP2 (Supporting): missense variants in the exon-6 glycine-rich domain are the established dominant disease mechanism for TARDBP.
4
Overall classification: VUS - PM1 and PM2 (moderate) plus PP2 (supporting) satisfy no ACMG/AMP pathogenic or benign combining rule.
Final determination: Generic ACMG/AMP 2015 fallback: 2 PM + 1 PP does not meet any combination threshold, so classified as 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 substitution, not a null variant class expected to trigger nonsense-mediated decay or abolish protein function.
pvs1_generic_framework generic_acmg_combination_rules
PS1 Not assessed Not assessed: no alternate nucleotide change producing the identical p.Gly295Ser amino acid substitution has been reported.
PS2 Not assessed Not assessed: no parental testing confirms a de novo origin of p.Gly295Ser.
PMID:19236453 PMID:21651514
PS3 Not assessed Not assessed: two functional studies suggest abnormal effects, but neither used a validated assay with pathogenic/benign controls.
PMID:28335005 PMID:25090004
PS4 Not assessed Not assessed: two sporadic ALS observations lack the case-control comparison needed for a statistically significant enrichment analysis.
PMID:19236453 PMID:21651514
PM1 Met Met (Moderate): Gly295 lies in the exon-6 glycine-rich C-terminal domain, an established mutational hotspot for TARDBP-related ALS/FTLD.
PMID:19236453 PMID:21651514 PMID:20031275 PMID:25090004
PM2 Met Met (Moderate): extremely rare in gnomAD v4.1 at 2 of 1,613,954 alleles (AF 1.24e-06), below the 0.1% threshold.
gnomad_v4 gnomad_v2 gnomad_canada PMID:19236453
PM3 N/A Not applicable: PM3 requires a recessive mechanism, but TARDBP-related ALS/FTD is autosomal dominant.
clinvar PMID:19236453 PMID:21651514
PM4 N/A Not applicable: the missense substitution does not alter protein length, which PM4 requires.
pvs1_generic_framework generic_acmg_combination_rules
PM5 Not assessed Not assessed: p.Gly295Arg, reported at the same residue, is not established as Pathogenic/Likely Pathogenic.
PM6 Not assessed Not assessed: no evidence establishes that p.Gly295Ser arose de novo.
PMID:19236453 PMID:21651514
PP1 Not assessed Not assessed: no affected relatives carrying the variant were reported, so cosegregation cannot be evaluated.
PMID:19236453 PMID:21651514
PP2 Met Met (Supporting): missense variants in the exon-6 glycine-rich domain are the established dominant disease mechanism for TARDBP.
PMID:20031275 PMID:19236453
PP3 Not met Not met: REVEL score 0.501 falls below the >=0.644 pathogenic-supporting threshold.
revel bayesdel spliceai
PP4 Not assessed Not assessed: ALS is genetically heterogeneous and not highly specific to TARDBP-related disease.
PMID:19236453 PMID:21651514
PP5 Not met Not met: no ClinVar expert-panel Pathogenic/Likely Pathogenic assertion exists for this variant.
clinvar
BA1 Not met Not met: highest allele frequency is 1.7e-06, far below the >1% BA1 threshold.
gnomad_v4 gnomad_v2
BS1 Not met Not met: highest allele frequency is 1.7e-06, far below the >0.3% BS1 threshold.
gnomad_v4 gnomad_v2
BS2 Not assessed Not assessed: the two gnomAD carriers lack documented adult phenotype and disease status.
gnomad_v4 gnomad_v2
BS3 Not met Not met: available functional studies show abnormal, not normal, TDP-43 function.
PMID:28335005 PMID:25090004
BS4 Not assessed Not assessed: no unaffected carriers or informative non-segregation analysis were reported.
PMID:19236453 PMID:21651514
BP1 Not met Not met: TARDBP disease is driven by missense, not truncating, variants.
PMID:20031275
BP2 Not assessed Not assessed: no phase or parental data are available to evaluate a trans configuration.
clinvar PMID:19236453 PMID:21651514
BP3 N/A Not applicable: this missense substitution is not an in-frame indel in a repetitive region.
pvs1_generic_framework generic_acmg_combination_rules
BP4 Not met Not met: REVEL score 0.501 falls above the <=0.290 benign-supporting threshold.
revel bayesdel spliceai
BP5 Not assessed Not assessed: no molecularly established alternative cause of disease was reported.
PMID:19236453 PMID:21651514
BP6 Not met Not met: no ClinVar expert-panel Benign/Likely Benign assertion exists for this variant.
clinvar
BP7 N/A Not applicable: BP7 applies only to synonymous variants, and this is a missense substitution.
generic_acmg_combination_rules
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