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TAF1c.3811_3812delinsCCUncertain significance
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Variant interpretation report

TAF1 c.3811_3812delinsCC, p.(Lys1271Pro)

NM_004606.4:c.3811_3812delinsCC NP_004597.2:p.(Lys1271Pro) View identifiers
Classification
Uncertain significance

Variant description:

No variant summary was recorded for this case.

Five-step scale from benign to pathogenic. This variant is uncertain. Select a step to read what it means.

Uncertain.The recorded classification is uncertain significance.

In plain language

Gene-level background from the recorded interpretation.

About TAF1

No gene-level summary was recorded for this case.

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.
01The reasoning

How it was classified

The recorded framework is Not recorded. The criteria and strengths shown below come from the saved assessment; this page does not recalculate the classification.

Recorded applied criteria

The applied criteria and their strengths are shown as assessed under the stated framework.

Pathogenic evidence criteria: 1 Benign evidence criteria: 0
Pathogenic criteria applied · 1
PM2Moderate
PM2 · moderate

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.

Benign criteria applied · 0

No benign criterion marked as applied in the recorded assessment.

Recorded classification: Uncertain significance

gene-specific framework lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback; applied criteria: PM2 moderate; combination = 1 moderate, which maps to VUS.

02The sources

Evidence at a glance

Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.

SpliceAI score
0.010 maximum delta

Recorded SpliceAI maximum delta score: 0.010. Refer to the recorded PP3/BP4 rationale for interpretation.

No listed criterion applied SpliceAI ↗
ClinVar submissions
Not recorded

A ClinVar laboratory submission summary was not recorded.

Context only ClinVar ↗
Functional evidence
Statement recorded

OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. TAF1, a transcription factor, is infrequently altered in cancer.

No listed criterion applied OncoKB ↗
COSMIC
Cancer Hotspots
Somatic evidence
No matching record reported

COSMIC could not be reviewed because the browser session was redirected to the login page before search results were available.

Cancer Hotspots

This variant does not lie in a statistically significant hotspot.

Context only
COSMIC ↗Cancer Hotspots ↗
For specialists

Technical detail

ACMG/AMP criteria under Not recorded, with the data and sources behind each one.

29 criteria with recorded statuses: 1 met · 25 not met · 0 not assessed · 3 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.

Pathogenic
PVS1PS1PS2PS3PS4PM1PM2PM3PM4PM5PM6PP1PP2PP3PP4PP5PS5
Benign
BA1BS1BS2BS3BS4BP1BP2BP3BP4BP5BP6BP7
Met Not met Not assessed Not applicable

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).

Met · 1

PM2 ModerateNM_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. Details ▾Hide ▴
Evidence considered
  • Absent from gnomAD v2.1 (exomes).
  • Absent from gnomAD v4.1 (exomes).
  • Absent from gnomAD-Canada v1.0 (genomes).
Sources
gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗

Not met · 25 · evaluated, threshold not reached

PVS1 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). Details ▾Hide ▴
Evidence considered
  • Variant is an in-frame delins producing a missense change (Lys1271Pro)
  • not a null variant eligible for PVS1.
Sources
pvs1_generic_framework ↗pvs1_variant_assessment
PS1 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. Details ▾Hide ▴
Still missing
  • No previously established pathogenic variant with the same amino acid change at this position.
PS2 No de novo occurrence data with confirmed paternity and maternity is available for this variant. Details ▾Hide ▴
Still missing
  • No de novo data available for NM_004606.4:c.3811_3812delinsCC.
PS3 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. Details ▾Hide ▴
Evidence considered
  • No functional assays performed on this variant or a systematically characterized range that includes residue 1271.
Still missing
  • No functional data available for this variant.
Sources
oncokb ↗
PS4 No case-control data or statistical evidence demonstrating enrichment of this variant in affected individuals versus controls is available. Details ▾Hide ▴
Still missing
  • No prevalence data in affected populations.
PM1 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. Details ▾Hide ▴
Evidence considered
  • Cancerhotspots.org reports no significant hotspot at this residue.
Still missing
  • No domain-level functional characterization of the region around residue 1271 in TAF1 available for this adjudication.
PM6 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. Details ▾Hide ▴
Still missing
  • No de novo reports for this variant.
PP1 No co-segregation data in multiple affected family members is available for this variant. Details ▾Hide ▴
Still missing
  • No family segregation data.
PP2 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. Details ▾Hide ▴
Evidence considered
  • HCI prior not available for TAF1.
Still missing
  • No constraint data for TAF1 missense variation.
PP3 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. Details ▾Hide ▴
Evidence considered
  • SpliceAI max delta 0.01: no splicing impact predicted.
  • REVEL and BayesDel scores not available for indel variants.
Still missing
  • No applicable in silico missense prediction scores for this indel.
Sources
spliceai ↗
PP4 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. Details ▾Hide ▴
Still missing
  • No phenotype data provided.
PP5 The variant is absent from ClinVar; no reputable source has reported this variant as pathogenic. No ClinVar variation ID or expert panel classification exists. Details ▾Hide ▴
Evidence considered
  • Variant is absent from ClinVar.
Sources
clinvar ↗
BA1 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. Details ▾Hide ▴
Evidence considered
  • Variant is absent from all gnomAD populations tested.
Sources
gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗
BS1 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. Details ▾Hide ▴
Evidence considered
  • Variant is absent from all gnomAD populations
  • frequency does not exceed BS1 threshold.
Sources
gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗
BS2 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). Details ▾Hide ▴
Evidence considered
  • Not observed in any gnomAD individual.
Still missing
  • No observation in healthy individuals.
Sources
gnomad_v2 ↗gnomad_v4 ↗
BS3 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. Details ▾Hide ▴
Still missing
  • No functional data available.
Sources
oncokb ↗
BS4 No family segregation data is available. BS4 requires lack of segregation in affected family members. Details ▾Hide ▴
Still missing
  • No segregation data.
BP1 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. Details ▾Hide ▴
Evidence considered
  • TAF1 disease is mediated by both missense (MRXS33) and loss-of-function (XDP) mechanisms.
BP2 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. Details ▾Hide ▴
Still missing
  • No trans observation data.
BP3 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. Details ▾Hide ▴
Still missing
  • No evidence that position 1271 is in a repetitive region without function.
BP4 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. Details ▾Hide ▴
Evidence considered
  • SpliceAI max delta 0.01: no splicing impact predicted.
  • REVEL/BayesDel not applicable for indel
  • no other benign in silico predictions available.
Still missing
  • Insufficient computational evidence to confidently predict benign impact.
Sources
spliceai ↗
BP5 No data are available indicating this variant has been observed in a case with an alternate molecular basis for disease. Details ▾Hide ▴
Still missing
  • No alternate molecular basis data.
BP6 The variant is absent from ClinVar; no reputable source has classified this variant as benign. Details ▾Hide ▴
Evidence considered
  • Variant is absent from ClinVar.
Sources
clinvar ↗
BP7 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. Details ▾Hide ▴
Evidence considered
  • Variant results in a missense change (Lys1271Pro)
  • not synonymous.
PS5 No reputable source has classified this variant as pathogenic. The variant is absent from ClinVar, and no published clinical reports describe it as pathogenic. Details ▾Hide ▴
Still missing
  • Absent from ClinVar
  • no external pathogenic classification.
Not applicable · 3· recorded as not applicable Show reasons ▾Hide reasons ▴
PM3 N/APM3 is for recessive disorders; TAF1-related disorders are X-linked. Skipped per instruction. Details ▾Hide ▴

No further detail was recorded.

PM4 N/APM4 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. Details ▾Hide ▴

No further detail was recorded.

PM5 N/ANo 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. Details ▾Hide ▴
Evidence considered
  • Automated harvesting found no same-residue PM5 candidates at position 1271.
Sources
pm5_candidates

Identifiers

Gene
TAF1
Transcript
NM_004606.4
Coding (HGVS c.)
NM_004606.4:c.3811_3812delinsCC
Protein (HGVS p.)
NP_004597.2:p.(Lys1271Pro)
GRCh38
chrX:71398702 AA>CC
GRCh37
chrX:70618552 AA>CC

Gene diagram

Every interpreted variant in TAF1, mapped onto the exon structure of NM_004606.4. Select a row to find it on the plot.

TAF1NM_004606.4
Fetching transcript structure from UCSC…
gnomAD v4.1 Allele count data not recorded
gnomAD v2.1 Allele count data not recorded
gnomAD-Canada v1.0 Allele count data not recorded

Statements

gnomAD v4.1

Absent from gnomAD v4.1.

gnomAD v2.1

Absent from gnomAD v2.1.

gnomAD-Canada

Absent from gnomAD-Canada v1.0.

SpliceAI and Pangolin

SpliceAI acceptor lossat -92 bp
0.010
SpliceAI acceptor gainat -181 bp
0.000
SpliceAI donor lossat +39 bp
0.000
SpliceAI donor gainat +35 bp
0.000

Other predictors

REVEL
Not available
BayesDel
Not available

How the predictions were used

PP3 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. Details ▾Hide ▴
Evidence considered
  • SpliceAI max delta 0.01: no splicing impact predicted.
  • REVEL and BayesDel scores not available for indel variants.
Still missing
  • No applicable in silico missense prediction scores for this indel.
Sources
spliceai ↗
BP4 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. Details ▾Hide ▴
Evidence considered
  • SpliceAI max delta 0.01: no splicing impact predicted.
  • REVEL/BayesDel not applicable for indel
  • no other benign in silico predictions available.
Still missing
  • Insufficient computational evidence to confidently predict benign impact.
Sources
spliceai ↗
BP7 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. Details ▾Hide ▴
Evidence considered
  • Variant results in a missense change (Lys1271Pro)
  • not synonymous.

Statement

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01).

0 paper records listed. No publication is explicitly linked to an applied criterion in the recorded metadata.

Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.

gnomAD v4.1 Captured gnomAD v4.1 source record Open source ↗
gnomAD v2.1 Captured gnomAD v2.1 source record Open source ↗
SpliceAI Lookup Recorded maximum delta 0.010 Open source ↗
ClinVar Captured ClinVar source record Open source ↗
COSMIC Captured COSMIC source record Open source ↗
Cancer hotspots Captured Cancer Hotspots source record Open source ↗
OncoKB Captured OncoKB source record Open source ↗

All source links

Statements for reports

The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.

gnomAD v4.1

Absent from gnomAD v4.1.

gnomAD v2.1

Absent from gnomAD v2.1.

gnomAD-Canada

Absent from gnomAD-Canada v1.0.

ClinVar

This variant is absent from ClinVar.

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01).

Functional

OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. TAF1, a transcription factor, is infrequently altered in cancer.

Somatic

This variant does not lie in a statistically significant hotspot. COSMIC could not be reviewed because the browser session was redirected to the login page before search results were available.

Cancer Hotspots

This variant does not lie in a statistically significant hotspot.