PHF6 c.417_418+1delinsCGA, p.?
NM_001015877.1:c.417_418+1delinsCGA
Variant of Uncertain Significance (VUS)
The c.417_418+1delinsCGA variant in PHF6 disrupts the canonical splice donor site and is absent from population databases, with strong in silico support for splicing disruption. Applying PVS1 (Very Strong), PM2 (Moderate), and PP3 (Supporting) yields a Likely Pathogenic classification.
ACMG/AMP Criteria Applied
PVS1
PM2
PP3
Genetic Information
Gene & Transcript Details
Gene
PHF6
Transcript
NM_001015877.2
MANE Select
Total Exons
11
Strand
Forward (+)
Reference Sequence
NC_000023.10
Alternative Transcripts
| ID | Status | Details |
|---|---|---|
| NM_001015877.1 | RefSeq Select | 11 exons | Forward |
Variant Details
HGVS Notation
NM_001015877.1:c.417_418+1delinsCGA
Protein Change
?
Location
Exon 5
(Exon 5 of 11)
5'Exon Structure (11 total)3'
Functional Consequence
Loss of Function
Related Variants
Variant interpretation based on transcript NM_001015877.2
Genome Browser
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HGVS InputNM_001015877:c.417_418+1delinsCGA
Active Tracks
ConservationRefSeqClinVargnomAD
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Clinical Data
Population Frequency
Global Frequency
0.0 in 100,000
Extremely Rare
Global: 0.0%
0%
0.05%
0.1%
1%
5%
10%+
ACMG Criteria Applied
PM2
This variant is not present in gnomAD (PM2 criteria applies).
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
Computational Analysis
Pathogenicity Predictions
Predictor Consensus
Unknown
PP3 Applied
No
VCEP Guidelines
Applied ACMG/AMP Criteria (VCEP Specific)
PVS1
PVS1 (Very Strong)
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 or multi-exon deletion)'. The evidence for this variant shows alteration of the canonical +1 splice donor site (c.417_418+1delinsCGA) predicted to abolish normal splicing and result in loss of function. Therefore, this criterion is applied at Very Strong strength because it disrupts a canonical splice site in a gene with established LoF disease mechanism.
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 but different nucleotide change'. The evidence for this variant shows no previously established pathogenic variant resulting in the same amino acid change. Therefore, this criterion is not applied.
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 information on de novo occurrence for this variant. Therefore, this criterion is not applied.
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'. There are no functional studies available for this variant. Therefore, this criterion is not applied.
PS4
PS4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PS4 is: 'PS4 – Prevalence in affected individuals significantly increased compared with controls'. There are no case-control data demonstrating increased prevalence in affected individuals. Therefore, this criterion is not applied.
PM1
PM1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM1 is: 'PM1 – Located in a mutational hot spot or well-established functional domain without benign variation'. This variant is not located in a recognized mutational hotspot or critical domain without benign variation. 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) in population databases'. The evidence for this variant shows it is absent from gnomAD and other population databases. Therefore, this criterion is applied at Moderate strength because the variant is not observed in controls.
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'. PHF6 is associated with an X-linked disorder and there is no evidence of the variant being observed in trans with another pathogenic variant. 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'. This variant is predicted to affect splicing rather than cause an in-frame indel directly altering protein length. 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'. This variant does not produce a missense change. 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'. There is no available de novo data for this variant. 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'. There are no segregation data for this variant. 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'. This variant is not a missense change. Therefore, this criterion is not applied.
PP3
PP3 (Supporting)
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 (e.g., conservation, splicing impact)'. The evidence for this variant shows SpliceAI predicts a high impact on splicing (score 0.98). Therefore, this criterion is applied at Supporting strength because in silico tools strongly predict a deleterious splicing effect.
PP4
PP4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP4 is: 'PP4 – Patient's phenotype or family history highly specific for a disease with a single genetic etiology'. No phenotype or family history 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'. This variant is not reported in ClinVar or other reputable sources. 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'. This variant is absent from population databases and thus not at high frequency. 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 the disorder'. This variant is absent from population databases. 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 a healthy adult individual for a dominant disorder with full penetrance expected at an early age'. There is no evidence of this variant in healthy individuals. 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 are available. 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 where only LoF causes disease'. This variant is not a missense change. 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 dominant disorders or in cis with a pathogenic variant'. There is no evidence of such configuration. 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 deletions/insertions in a repetitive region without known function'. This variant affects splicing and is not an in-frame indel in a repetitive region. Therefore, this criterion is not applied.
BP4
BP4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP4 is: 'BP4 – Multiple lines of computational evidence suggest no impact on gene or gene product'. Computational evidence for this variant predicts a deleterious effect. Therefore, this criterion is not applied.
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 case data exist. 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'. This variant is not reported as benign by any reputable source. 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 variant is not synonymous. Therefore, this criterion is not applied.