CUX1 c.4403A>T, p.Gln1468Leu
NM_001202543.1:c.4403A>T
Variant of Uncertain Significance (VUS)
The CUX1 c.4403A>T (p.Q1468L) variant is classified as VUS due to moderate-level PM2 (rare in population) and supporting-level BP4 (benign computational predictions), with no additional criteria met to resolve pathogenicity or benignity.
ACMG/AMP Criteria Applied
PM2
BP4
Genetic Information
Gene & Transcript Details
Gene
CUX1
Transcript
NM_001202543.1
Total Exons
24
Strand
Forward (+)
Reference Sequence
NC_000007.13
Alternative Transcripts
| ID | Status | Details |
|---|---|---|
| NM_001202543.2 | Alternative | 24 exons | Forward |
Variant Details
HGVS Notation
NM_001202543.1:c.4403A>T
Protein Change
Q1468L
Location
Exon 24
(Exon 24 of 24)
5'Exon Structure (24 total)3'
Functional Consequence
Loss of Function
Related Variants
No evidence of other pathogenic variants at position 1468 in gene CUX1
Variant interpretation based on transcript NM_001202543.1
Genome Browser
Loading genome browser...
HGVS InputNM_001202543:c.4403A>T
Active Tracks
ConservationRefSeqClinVargnomAD
Navigation tips: Use mouse to drag and zoom. Click on features for details.
Clinical Data
Global Frequency
0.0457%
Low Frequency
Highest in Population
European (Finnish)
0.422%
Common
Global: 0.0457%
European (Finnish): 0.422%
0%
0.05%
0.1%
1%
5%
10%+
Allele Information
Total: 122576Alt: 56Homozygotes: 0
ACMG Criteria Applied
PM2
This variant is present in gnomAD (MAF= 0.0457%, 56/122576 alleles, homozygotes = 0) and at a higher frequency in the European (Finnish) population (MAF= 0.422%, 43/10196 alleles, homozygotes = 0). The variant is rare (MAF < 0.1%), supporting PM2 criterion application.
Classification
Unknown
Publications (0)
No publication details.
Clinical Statement
Functional Impact
Functional Domain
Hotspot Status
Not a hotspot
Domain Summary
This variant is not located in a mutational hotspot or critical domain (0 mutations).
Related Variants in This Domain
No evidence of other pathogenic variants at position 1468 in gene CUX1
Computational Analysis
Pathogenicity Predictions
Predictor Consensus
Mixed/VUS
PP3 Applied
No
Additional Predictors
Pathogenic:
primateai: D
Benign:
CADD: 4.04polyphen_prediction: benignmetasvm: Tmetalr: T
Neutral: Show all
VCEP Guidelines
Applied ACMG/AMP Criteria (VCEP Specific)
PVS1
PVS1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PVS1 is: "PVS1 – Null variant in a gene where loss of function (LoF) is a known mechanism of disease (e.g., nonsense, frameshift, canonical ±1 or 2 splice sites, initiation codon, single exon or multiexon deletion)." The evidence for this variant shows it is a missense change (Q1468L) not predicted to create a null allele. Therefore, this criterion is not applied because the variant is not a predicted LoF.
PS1
PS1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PS1 is: "PS1 – Same amino acid change as a previously established pathogenic variant, regardless of nucleotide change." The evidence for this variant shows no previously established pathogenic variant at residue Q1468. Therefore, this criterion is not applied because there is no known pathogenic Q1468 variant.
PS2
PS2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PS2 is: "PS2 – De novo (both maternity and paternity confirmed) in a patient with the disease and no family history." There is no de novo occurrence data for this variant. Therefore, this criterion is not applied due to lack of de novo evidence.
PS3
PS3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PS3 is: "PS3 – Well-established functional studies supportive of a damaging effect on the gene or gene product." No functional assays of the Q1468L variant have been reported. Therefore, this criterion is not applied because required functional data are absent.
PS4
PS4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PS4 is: "PS4 – Prevalence of the variant in affected individuals is significantly increased compared with controls." There are no case‐control or affected‐individual data for this variant. Therefore, this criterion is not applied due to lack of prevalence data.
PM1
PM1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM1 is: "PM1 – Located in a mutational hot spot and/or critical and well‐established functional domain without benign variation." The Q1468 residue is not known to be in a defined mutational hotspot or critical domain. Therefore, this criterion is not applied.
PM2
PM2 (Moderate)
According to standard ACMG guidelines, the rule for PM2 is: "PM2 – Absent from controls (or at extremely low frequency if recessive)." The evidence for this variant shows a gnomAD MAF of 0.0457% (56/122,576 alleles) with no homozygotes. Therefore, this criterion is applied at Moderate strength because the variant is absent or extremely rare in population databases.
PM3
PM3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM3 is: "PM3 – Detected in trans with a pathogenic variant for a recessive disorder." This is not a recessive disorder context and no trans variant data are available. Therefore, this criterion is not applied.
PM4
PM4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM4 is: "PM4 – Protein length changes due to in-frame deletions/insertions or stop-loss variants." The variant is a missense substitution without protein length change. Therefore, this criterion is not applied.
PM5
PM5 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM5 is: "PM5 – Novel missense change at an amino acid residue where a different pathogenic missense change has been seen." No other pathogenic missense changes have been reported at Q1468. Therefore, this criterion is not applied.
PM6
PM6 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM6 is: "PM6 – Assumed de novo, but without confirmation of paternity and maternity." No de novo data exist. Therefore, this criterion is not applied.
PP1
PP1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP1 is: "PP1 – Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease." No segregation data are available. Therefore, this criterion is not applied.
PP2
PP2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP2 is: "PP2 – Missense variant in a gene with a low rate of benign missense variation and where missense variants are a common mechanism of disease." Insufficient evidence on CUX1 missense constraint and mechanism. Therefore, this criterion is not applied.
PP3
PP3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP3 is: "PP3 – Multiple lines of computational evidence support a deleterious effect on the gene or gene product." Computational predictions are predominantly benign (CADD, PolyPhen-2, MetaSVM, MetaLR) and SpliceAI predicts no splicing impact. Therefore, this criterion is not applied.
PP4
PP4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP4 is: "PP4 – Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology." No patient phenotype data are provided. Therefore, this criterion is not applied.
PP5
PP5 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP5 is: "PP5 – Reputable source reports variant as pathogenic, but without accessible evidence." The variant is not reported in ClinVar or other databases. Therefore, this criterion is not applied.
BA1
BA1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BA1 is: "BA1 – Allele frequency is too high for the disorder." The MAF of 0.0457% is below any BA1 threshold. Therefore, this criterion is not applied.
BS1
BS1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BS1 is: "BS1 – Allele frequency is greater than expected for disorder." The observed frequency is low. Therefore, this criterion is not applied.
BS2
BS2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BS2 is: "BS2 – Observed in healthy individuals for a dominant disorder with full penetrance expected early." No data on healthy adult observations. Therefore, this criterion is not applied.
BS3
BS3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BS3 is: "BS3 – Well-established functional studies show no damaging effect on protein function or splicing." No functional studies exist. Therefore, this criterion is not applied.
BS4
BS4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BS4 is: "BS4 – Lack of segregation in affected family members." No segregation data are available. Therefore, this criterion is not applied.
BP1
BP1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP1 is: "BP1 – Missense variant in a gene for which only loss of function is known to cause disease." Mechanism for CUX1 is not fully established. Therefore, this criterion is not applied.
BP2
BP2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP2 is: "BP2 – Observed in trans with a pathogenic variant for a dominant disorder or in cis with a pathogenic variant." No such data are available. Therefore, this criterion is not applied.
BP3
BP3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP3 is: "BP3 – In-frame indels in a repetitive region without known function." This is not an indel. Therefore, this criterion is not applied.
BP4
BP4 (Supporting)
According to standard ACMG guidelines, the rule for BP4 is: "BP4 – Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, splicing impact, etc.)." The evidence shows benign in silico predictions (CADD, PolyPhen-2, MetaSVM, MetaLR) and a SpliceAI score of 0. Therefore, this criterion is applied at Supporting strength because computational tools consistently predict no deleterious effect.
BP5
BP5 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP5 is: "BP5 – Variant found in a case with an alternate molecular basis for disease." No such reporting. Therefore, this criterion is not applied.
BP6
BP6 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP6 is: "BP6 – Reputable source reports variant as benign, but without accessible evidence." No such reports exist. Therefore, this criterion is not applied.
BP7
BP7 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP7 is: "BP7 – Synonymous variant with no predicted impact on splicing." This is a missense variant. Therefore, this criterion is not applied.