Variant classification summary

NM_001015877.1:c.834+53_834+58delAATTTA

PHF6 · NP_001015877.1:p.? · NM_001015877.1

GRCh37: chrX:133549198 CTTTAAA>C · GRCh38: chrX:134415168 CTTTAAA>C

Gene: PHF6 Transcript: NM_001015877.1

Final call

Likely Benign

PM2 supporting BP4 supporting benign BP6 supporting benign BP7 supporting benign

Variant details

Gene

PHF6

Transcript

NM_001015877.1

Protein

NP_001015877.1:p.?

gnomAD AF

2.073305445992881e-05 (v4.1)

ClinVar

Benign

OncoKB

Classification rationale

Interpretation summary

Generated evidence synthesis

1

NM_001015877.1:c.834+53_834+58delAATTTA is an intronic deletion in PHF6 located 53 bases into intron 8, beyond the conserved splice consensus region.

2

SpliceAI predicts no significant splice impact (max delta score 0.01), consistent with a benign interpretation (BP4).

3

This variant is present in gnomAD v2.1 at low frequency (0.0101%, 18/178,302 alleles) and in gnomAD v4.1 (0.0021%, 25/1,205,804 alleles), below the 0.1% PM2 threshold.

4

ClinVar classifies this variant as Benign (Ambry Genetics, criteria provided) and Likely benign (PreventionGenetics), supporting a benign interpretation (BP6).

5

The intronic deletion at +53 position is well outside the conserved splice donor/acceptor consensus, and SpliceAI confirms no predicted splice effect (BP7).

6

With three supporting benign criteria (BP4, BP6, BP7) met, exceeding the two supporting benign criteria threshold for Likely Benign under generic ACMG/AMP 2015 combination rules, the variant is classified as Likely Benign.

Final determination: Generic ACMG/AMP 2015 fallback rules support a Likely Benign classification because either one strong benign criterion plus one supporting benign criterion, or at least two supporting benign criteria, are present.

Criteria assessment

ACMG/AMP criteria review

Criteria shown when status is available

All criteria require review: For research and educational purposes only.

Criterion	Status	Rationale	Evidence used
PVS1	N/A	This variant is an intronic deletion (c.834+53_834+58del) located 53 bases into intron 8. It does not fall into the default null-variant buckets of nonsense, frameshift, or canonical ±1,2 splice consensus variants. The generic PVS1 framework (PMC6185798) does not apply.	pvs1_variant_assessment pvs1_generic_framework
PS1	N/A	No known pathogenic variant has been established at the same nucleotide change as this intronic deletion.
PS2	N/A	No de novo data are available for this variant.
PS3	Not assessed	No functional studies have been identified that assess the biological effect of this intronic deletion.
PS4	Not met	No case-control or patient phenotype enrichment data are available for this variant. ClinVar submitters (Ambry Genetics, PreventionGenetics) reported classifications of Benign and Likely benign from clinical testing without providing case counts or phenotype details specific to this variant.	clinvar
PS5	N/A	ClinVar classifies this variant as Benign and Likely benign. No reputable source has classified this variant as pathogenic.	clinvar
PM1	N/A	This intronic variant is not located within a recognized functional domain or established mutational hotspot.
PM2	Met	This variant is present in gnomAD v2.1 at very low frequency (AF=0.0101%, 18/178,302 alleles, 0 homozygotes) and in gnomAD v4.1 at 0.0021% (25/1,205,804 alleles). Both frequencies fall below the 0.1% PM2 threshold, and the variant is absent from gnomAD-Canada. However, as a deep intronic variant with no confirmed functional consequence, the weight is limited to supporting level.	gnomad_v2 gnomad_v4 gnomad_canada
PM3	N/A	No data on biallelic/in trans observations; variant is hemizygous on chromosome X.
PM4	N/A	This is an intronic deletion that does not alter protein length; PM4 is restricted to non-repeat in-frame deletions/insertions and stop-loss variants.
PM5	N/A	This is not a missense variant; PM5 requires a novel missense change at a residue where a different pathogenic missense change has been established.	pm5_candidates
PM6	N/A	No de novo observation data are available for this variant.
PP1	Not assessed	No segregation data are available for this variant.
PP2	N/A	This is not a missense variant; PP2 applies only to missense variants in genes with a low rate of benign missense variation.
PP3	Not met	SpliceAI predicts no significant splice impact for this intronic deletion (max delta score = 0.01). REVEL and BayesDel are not applicable as this is not a single nucleotide variant. No in silico tool predicts a pathogenic effect.	spliceai
PP4	Not assessed	No patient phenotype data are available to assess specificity for a PHF6-associated disorder.
PP5	Not met	ClinVar classifies this variant as Benign and Likely benign from clinical laboratory submissions. No reputable source has classified this variant as pathogenic. The ClinVar-associated publications are policy and guideline papers on newborn screening and genetic testing that do not mention PHF6 or this specific variant.	clinvar
BA1	Not met	The highest population frequency in gnomAD v2.1 is 0.068% (Admixed American, 18/26,371 alleles) and in gnomAD v4.1 is 0.051% (Admixed American, 23/45,214 alleles). Both are well below the 1% BA1 threshold.	gnomad_v2 gnomad_v4
BS1	Not met	The highest population frequency in gnomAD v2.1 is 0.068% (Admixed American) and in gnomAD v4.1 is 0.051% (Admixed American). Both are below the 0.3% BS1 threshold.	gnomad_v2 gnomad_v4
BS2	Not assessed	No specific data on observation of this variant in healthy adults are available beyond population database frequencies.
BS3	Not assessed	No functional assays have been identified that demonstrate no deleterious effect of this intronic deletion. SpliceAI prediction of no splice impact (delta 0.01) is computational evidence (assessed under BP4), not direct functional data.
BS4	Not assessed	No segregation data are available to evaluate lack of cosegregation with disease.
BP1	N/A	This is not a missense variant; BP1 applies to missense variants in genes where truncation is the primary disease mechanism.
BP2	N/A	No data on observation in trans with a pathogenic variant; variant is on chromosome X.
BP3	N/A	This is an intronic deletion, not an in-frame indel in a repetitive coding region.
BP4	Met	SpliceAI predicts no significant splice impact for this intronic deletion (max delta score = 0.01). Multiple in silico tools agree that this deep intronic variant is unlikely to alter splicing, supporting a benign interpretation. REVEL and BayesDel are not applicable as this is not a single nucleotide variant.	spliceai
BP5	N/A	No data available on an alternative molecular basis for disease in a proband with this variant.
BP6	Met	This variant has been reported in ClinVar as Benign by Ambry Genetics (criteria provided, single submitter) and as Likely benign by PreventionGenetics (Variation ID 2396348). Multiple clinical laboratories have independently classified this variant as benign or likely benign.	clinvar
BP7	Met	This variant is an intronic deletion at position +53 of intron 8, well beyond the conserved splice donor/acceptor consensus (±1,2). SpliceAI confirms no predicted splice impact (max delta = 0.01). Deep intronic variants at this distance from the splice junction, without predicted splice effects, are consistent with a benign interpretation.	spliceai

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