NM_000546.6:c.919+4A>G is an intronic variant at the +4 position of intron 8 in TP53, evaluated under the ClinGen TP53 VCEP Specifications v2.4.0. The variant is absent from gnomAD v2.1 and v4.1, supporting PM2_Supporting.1 SpliceAI predicts no splicing impact (max delta score 0.00). As an intronic variant outside the ±1,2 canonical splice positions with SpliceAI ≤0.1, BP4_Supporting is met.2 PVS1 is not applicable as the variant lies outside the canonical ±1,2 splice donor/acceptor positions addressed by the VCEP PVS1 flowchart. PS3/BS3 functional codes are not applicable as they address missense variants and small in-frame deletions only. The variant is not located in a VCEP-specified mutational hotspot and has no amino acid change, so PM1 and PM5 are not applicable.3 With one pathogenic supporting code (PM2_Supporting, +1 point) and one benign supporting code (BP4_Supporting, -1 point), the total point value is 0. Under the Tavtigian point-based system adopted by the TP53 VCEP v2.4.0, a score of 0 falls in the range of Uncertain Significance (-1 to 5 points).4
TP53
Final classification
VUS
TP53 c.919+4A>G · p.?
TP53
NM_000546.6:c.919+4A>G is an intronic variant at the +4 position of intron 8 in TP53, evaluated under the ClinGen TP53 VCEP Specifications v2.4.0. The variant is absent from gnomAD v2.1 and v4.1, supporting PM2_Supporting.
Tavtigian et.al., 2020 - Bayesian adaptation of Richards et.al., 2015 v2.4.0 point-based framework: PM2 supporting (+1) + BP4 supporting (-1) = 0 points, which maps to VUS.
Classification rationale
PM2
BP4
VUS
TP53 c.919+4A>G
PM2 + BP4
→
VUS
Gene diagram
· NM_000546.6 · variants mapped to exon structure
TP53
NM_000546.6
Fetching transcript structure from UCSC…
Applied criteria · 2 applied · 11 assessed
Applied · 2
Strength
Supporting
Moderate
Strong
Very strong
✓
PM2
supporting
Pathogenic
NM_000546.6:c.919+4A>G is absent from gnomAD v2.1 (exomes) and gnomAD v4.1 (exomes/genomes), meeting the TP53 VCEP PM2_Supporting threshold of allele frequency <0.00003 (0.003%).
Absent from gnomAD v2.1Absent from gnomAD v4.1
✓
BP4
supporting
Benign
NM_000546.6:c.919+4A>G is an intronic variant outside the ±1,2 canonical splice positions. Per the TP53 VCEP BP4 rule, intronic variants outside ±1,2 with SpliceAI ≤0.1 qualify for BP4_Supporting. The SpliceAI max delta score is 0.00, meeting this threshold.
Intronic variant at +4 position (outside ±12)SpliceAI max delta 0.00 ≤0.1
Assessed · not applied
Pathogenic
PS1
No other nucleotide substitutions at the c.919+4 position have been classified as pathogenic or likely pathogenic under the TP53 VCEP specifications.
PS2
No de novo observations for NM_000546.6:c.919+4A>G were identified in the available literature.
PS4
No proband data with Li-Fraumeni syndrome-associated cancers were available for NM_000546.6:c.919+4A>G.
PP1
No cosegregation data were available for NM_000546.6:c.919+4A>G.
PP3
For intronic splice variants outside the ±1,2 canonical positions, the TP53 VCEP PP3 rule requires SpliceAI ≥0.2.
PP4
No observations of NM_000546.6:c.919+4A>G with variant allele fraction (VAF) data were available.
Benign
BA1
The TP53 VCEP BA1 rule requires a filtering allele frequency (FAF) ≥0.001 (0.1%) in gnomAD continental subpopulations (excluding founder-influenced groups).
BS1
The TP53 VCEP BS1 rule requires a filtering allele frequency (FAF) ≥0.0003 (0.03%) but <0.001 in gnomAD continental subpopulations.
BS2
No data were available on unrelated females ≥60 years of age without cancer carrying NM_000546.6:c.919+4A>G.
BS4
No segregation data were available to assess lack of segregation in affected family members.
BP7
The TP53 VCEP BP7_Supporting rule requires an intronic variant at or beyond +7 to -21 positions with SpliceAI ≤0.1 and BP4 met.
N/A · 12
PVS1 · PS3 · PM1 · PM5 · PM6 · PP2 · PP5 · BS3 · BP1 · BP2 · BP5 · BP6
Research & evidence
Population frequency
gnomAD v4.1
gnomAD v2.1
v4.1
Absent from gnomAD v4.1.
v2.1
Absent from gnomAD v2.1.
🇨🇦 CA
This variant is absent from gnomAD-Canada.
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
gnomAD v2.1
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
gnomAD Canada 🇨🇦
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00).
Functional
No data
No calibrated functional assay or RNA evidence was identified for this variant.
COSMIC
Somatic evidence
COSMIC
This variant has not previously been reported in somatic cancers (COSMIC).
Hotspots
This variant does not lie in a statistically significant cancer hotspot.
Sources & reference links