NM_004606.4:c.3811_3812delinsCC

TAF1 · NP_004597.2:p.(Lys1271Pro) · NM_004606.4

GRCh37: chrX:70618552 AA>CC · GRCh38: chrX:71398702 AA>CC

Gene: TAF1 Transcript: NM_004606.4

Final call

VUS

PM2 moderate

Variant details

Gene

TAF1

Transcript

NM_004606.4

Protein

NP_004597.2:p.(Lys1271Pro)

gnomAD AF

ClinVar

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

NM_004606.4:c.3811_3812delinsCC (p.Lys1271Pro) is an in-frame deletion-insertion in TAF1 resulting in a missense substitution at codon 1271.

This variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada v1.0, meeting PM2 at moderate strength.

The variant is absent from ClinVar, providing no external pathogenic or benign classification.

No variant-specific functional data, segregation data, de novo reports, or case-control studies are available for this variant.

In silico splice prediction (SpliceAI max delta 0.01) suggests no splicing impact; REVEL and BayesDel are not applicable to this indel variant.

TAF1 loss of function is an established disease mechanism (X-linked dystonia-parkinsonism via SVA retrotransposon insertion, and missense variants cause X-linked syndromic intellectual disability MRXS33); however, this variant is a missense change, not a null variant, so PVS1 does not apply.

Overall, only one moderate pathogenic criterion (PM2) is met. Per generic ACMG/AMP 2015 combination rules, a single moderate criterion is insufficient for classification as likely pathogenic; the variant is classified as a Variant of Uncertain Significance (VUS).

Final determination: Generic ACMG/AMP 2015 fallback rules do not meet benign, likely benign, likely pathogenic, or pathogenic combination thresholds, so the variant is classified as Variant of 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	Not met	NM_004606.4:c.3811_3812delinsCC results in an in-frame deletion-insertion (p.Lys1271Pro), which is a missense substitution, not a null variant. The variant does not fall into the default generic PVS1 null-variant buckets of nonsense, frameshift, or canonical splice consensus disruption per ClinGen SVI recommendations (PMC6185798).	pvs1_generic_framework pvs1_variant_assessment
PS1	Not met	No alternative nucleotide change resulting in the same amino acid substitution (Lys1271Pro) has been reported as pathogenic. No comparator variant is available to satisfy PS1.
PS2	Not met	No de novo occurrence data with confirmed paternity and maternity is available for this variant.
PS3	Not met	No variant-specific or systematic range functional data is available for NM_004606.4:c.3811_3812delinsCC (p.Lys1271Pro). REVEL and BayesDel scores are not applicable to this indel variant. OncoKB reports unknown oncogenic effect with no variant-specific reviewed functional evidence.	oncokb
PS4	Not met	No case-control data or statistical evidence demonstrating enrichment of this variant in affected individuals versus controls is available.
PS5	Not met	No reputable source has classified this variant as pathogenic. The variant is absent from ClinVar, and no published clinical reports describe it as pathogenic.
PM1	Not met	Residue 1271 does not lie within a statistically significant mutational hotspot per cancerhotspots.org. Without CSPEC/VCEP domain mapping for TAF1 or specific evidence that position 1271 falls within a well-characterized critical functional domain, PM1 cannot be applied.
PM2	Met	NM_004606.4:c.3811_3812delinsCC is absent from gnomAD v2.1, v4.1, and gnomAD-Canada v1.0 population databases. This absence supports pathogenicity under generic ACMG/AMP PM2 at moderate strength.	gnomad_v2 gnomad_v4 gnomad_canada
PM4	N/A	PM4 applies to in-frame deletions/insertions that change protein length. NM_004606.4:c.3811_3812delinsCC is a deletion-insertion that preserves coding frame and does not alter protein length; it results in a missense substitution (p.Lys1271Pro), not a length change.
PM5	N/A	No same-residue comparator missense variants classified as pathogenic were identified in ClinVar for codon 1271 of TAF1. PM5 requires a different pathogenic missense change at the same residue.	pm5_candidates
PM6	Not met	No de novo occurrence (without confirmed paternity and maternity) has been reported for this variant. No published literature describes a de novo case of NM_004606.4:c.3811_3812delinsCC.
PP1	Not met	No co-segregation data in multiple affected family members is available for this variant.
PP2	Not met	No constraint metrics (Z-score, missense depletion) for TAF1 are available to determine a low rate of benign missense variation. HCI prior score was not found for this gene. Without evidence that TAF1 has a low rate of benign missense variation, PP2 cannot be applied.
PP3	Not met	In silico prediction tools (REVEL, BayesDel) are not applicable to this indel variant. SpliceAI predicts no significant splice impact (max delta score 0.01). No computational evidence supports a deleterious effect.	spliceai
PP4	Not met	No patient phenotype or family history data is available for this case. PP4 requires a phenotype that is highly specific for a disease with a single genetic etiology.
PP5	Not met	The variant is absent from ClinVar; no reputable source has reported this variant as pathogenic. No ClinVar variation ID or expert panel classification exists.	clinvar
BA1	Not met	NM_004606.4:c.3811_3812delinsCC is absent from gnomAD v2.1, v4.1, and gnomAD-Canada. The allele frequency is 0%, well below the >1% generic BA1 threshold for common benign variants.	gnomad_v2 gnomad_v4 gnomad_canada
BS1	Not met	The variant is absent from gnomAD, with an allele frequency of 0%. This does not exceed the >0.3% generic BS1 threshold for allele frequency greater than expected for the disorder.	gnomad_v2 gnomad_v4 gnomad_canada
BS2	Not met	The variant has not been observed in any individual in gnomAD, whether affected or healthy. BS2 requires observation in a healthy adult individual (homozygous for recessive, hemizygous for X-linked, or heterozygous for dominant disorders with full penetrance).	gnomad_v2 gnomad_v4
BS3	Not met	No in vitro or in vivo functional studies demonstrating no damaging effect on protein function or splicing are available for this variant. OncoKB reports unknown oncogenic effect with no variant-specific functional evidence.	oncokb
BS4	Not met	No family segregation data is available. BS4 requires lack of segregation in affected family members.
BP1	Not met	BP1 applies to missense variants in genes for which primarily truncating variants are known to cause disease. Published literature indicates that both missense and loss-of-function variants in TAF1 are associated with disease (e.g., missense mutations cause X-linked syndromic intellectual disability MRXS33, while SVA retrotransposon insertion causes X-linked dystonia-parkinsonism). TAF1 disease mechanism is not limited to truncating variants, so BP1 does not apply.
BP2	Not met	No observation in trans with a pathogenic variant has been reported. TAF1 is X-linked, making BP2 generally less applicable, but no relevant data exists in any case.
BP3	Not met	BP3 applies to in-frame deletions/insertions in repetitive regions without known function. Although the variant is an in-frame delins, there is no evidence that residue 1271 lies within a repetitive region of TAF1 that lacks functional significance.
BP4	Not met	SpliceAI predicts no splicing impact (max delta score 0.01), but REVEL and BayesDel scores are unavailable for this indel variant. A single benign computational prediction is insufficient to meet BP4, which requires multiple lines of computational evidence suggesting no impact.	spliceai
BP5	Not met	No data are available indicating this variant has been observed in a case with an alternate molecular basis for disease.
BP6	Not met	The variant is absent from ClinVar; no reputable source has classified this variant as benign.	clinvar
BP7	Not met	BP7 applies to synonymous variants with no predicted splice impact. NM_004606.4:c.3811_3812delinsCC results in a missense amino acid substitution (p.Lys1271Pro), not a synonymous change.
PM3	N/A	PM3 is for recessive disorders; TAF1-related disorders are X-linked. Skipped per instruction.

Disclaimer: The content and results provided by LYFE Sciences are for research and educational purposes only and must not be used as a substitute for professional medical judgment, diagnosis, or treatment. Always consult a qualified healthcare professional before making any clinical decisions.