NM_001904.4:c.-48-3dupT is a single-nucleotide T duplication in the 5' UTR of CTNNB1, 48 bases upstream of the initiation codon. It is present in gnomAD v4.1 at an extremely low allele frequency of 0.00057% (9/1,586,636 alleles, no homozygotes) and is absent from gnomAD v2.1 and gnomAD-Canada v1.0.1 The variant is absent from ClinVar and has not been reported in the published literature. No functional studies, segregation data, de novo observations, or case-control comparisons are available. SpliceAI predicts no significant splicing impact (max delta = 0.01).2 The variant has been observed once in somatic cancers (COSMIC COSV115288055), but this does not inform germline pathogenicity. Only PM2 (supporting) is met. With only one supporting pathogenic criterion and no benign criteria met, this variant is classified as a Variant of Uncertain Significance (VUS) under ACMG/AMP 2015 generic rules.3
CTNNB1
Final classification
VUS
CTNNB1 c.-48-3dup · p.?
CTNNB1
NM_001904.4:c.-48-3dupT is a single-nucleotide T duplication in the 5' UTR of CTNNB1, 48 bases upstream of the initiation codon. It is present in gnomAD v4.1 at an extremely low allele frequency of 0.00057% (9/1,586,636 alleles, no homozygotes) and is absent from gnomAD v2.1 and gnomAD-Canada v1.0.
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 supporting; combination = 1 supporting, which maps to VUS.
Classification rationale
PM2
VUS
CTNNB1 c.-48-3dup
PM2
→
VUS
Gene diagram
· NM_001904.4 · variants mapped to exon structure
CTNNB1
NM_001904.4
Fetching transcript structure from UCSC…
Applied criteria · 1 applied · 18 assessed
Applied · 1
Strength
Supporting
Moderate
Strong
Very strong
✓
PM2
supporting
Pathogenic
This variant is present in gnomAD v4.1 at an extremely low allele frequency of 5.67×10⁻⁶ (9/1,586,636 alleles, 0.00057%), well below the 0.1% threshold for PM2. It is absent from gnomAD v2.1 and gnomAD-Canada v1.0. No homozygotes observed.
gnomAD v4.1 AF = 5.67e-06 (9/1586636)
Assessed · not applied
Pathogenic
PS2
No de novo occurrence data available.
PS3
No well-established functional studies available for this variant.
PS4
No case-control data available.
PM1
The variant is located in the 5' UTR (c.-48-3dup), not within a known mutational hotspot or critical functional domain of CTNNB1.
PM6
No de novo occurrence data available.
PP1
No co-segregation data available.
PP3
Multiple lines of computational evidence supporting a deleterious effect are required.
PP4
No patient phenotype or family history data specific to this variant are available.
PP5
This variant is absent from ClinVar.
Benign
BA1
Allele frequency in gnomAD v4.1 is 5.67×10⁻⁶ (0.00057%), far below the 1% BA1 threshold.
BS1
Allele frequency in gnomAD v4.1 is 5.67×10⁻⁶ (0.00057%), far below the 0.3% BS1 threshold.
BS2
Nine alleles are observed in gnomAD v4.1, which excludes individuals with severe pediatric disease.
BS3
No well-established functional studies demonstrating no deleterious effect are available for this variant.
BS4
No non-segregation data available.
BP2
No data on observation in trans with a pathogenic variant.
BP4
Multiple lines of computational evidence suggesting no impact are required.
BP5
No data on an alternate molecular basis for disease in a case carrying this variant.
BP6
This variant is absent from ClinVar.
N/A · 9
PVS1 · PS1 · PM3 · PM4 · PM5 · PP2 · BP1 · BP3 · BP7
Research & evidence
Population frequency
gnomAD v4.1
gnomAD v2.1
v4.1
This variant is present in gnomAD v4.1 (AF= 5.67238e-06; MAF= 0.00057%, 9/1586636 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 7.78962e-06; MAF= 0.00078%, 9/1155384 alleles, homozygotes = 0); grpmax FAF= 3.67e-06.
v2.1
Absent from gnomAD v2.1.
🇨🇦 CA
Absent from gnomAD-Canada v1.0.
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
0.00057%
· 9 / 1,586,636
0 hom · FAF 0.00037%
0 hom · FAF 0.00037%
European (non-Finnish) 9 / 1,155,384 |
0.00078% |
+ 9 not observed (Remaining individuals, Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American)
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 = 0.01).
Functional
No data
No calibrated functional assay or RNA evidence was identified for this variant.
COSMIC
Somatic evidence
COSMIC
This variant has previously been reported in somatic cancers (COSMIC; COSV115288055, n = 1 times).
Hotspots
This variant does not lie in a statistically significant cancer hotspot.
Sources & reference links