PHF6c.834+53_834+58delLikely benign

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Variant interpretation report

PHF6 c.834+53_834+58del, p.?

NM_001015877.1:c.834+53_834+58del NP_001015877.1:p.? View identifiers

Classification

Likely benign

Variant description:

No variant summary was recorded for this case.

Five-step scale from benign to pathogenic. This variant is likely benign. Select a step to read what it means.

Likely benign.A likely benign classification under the recorded framework.

In plain language

Gene-level background from the recorded interpretation.

About PHF6

No gene-level summary was recorded for this case.

Key facts

Evidence used: 3 supporting (benign) · 1 supporting (pathogenic)
Expert rules: Not recorded
Other laboratories (ClinVar): 1 Benign · 1 Likely benign
Pipeline record: 26 Jun 2026 · version 7.0.0

Evidence considered

View criteria

Applied evidence criteria

PM2 (supporting): 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.
BP4 (supporting): 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.
BP6 (supporting): 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.
BP7 (supporting): 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.

LYFE Sciences is an AI system, and it can make mistakes. Criteria may be applied incorrectly, sources may be misread, and a confident-looking classification can still be wrong. Double-check every criterion and its underlying evidence before relying on any call.

01The reasoning

How it was classified

The recorded framework is Not recorded. The criteria and strengths shown below come from the saved assessment; this page does not recalculate the classification.

Recorded applied criteria

The applied criteria and their strengths are shown as assessed under the stated framework.

Pathogenic evidence criteria: 1 Benign evidence criteria: 3

Pathogenic criteria applied · 1

PM2Supporting

PM2 · supporting

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.

Benign criteria applied · 3

BP4Supporting

BP4 · supporting

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.

BP6Supporting

BP6 · supporting

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.

BP7Supporting

BP7 · supporting

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.

Recorded classification: Likely benign

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, BP4 supporting benign, BP6 supporting benign, BP7 supporting benign; combination = 1 supporting + 3 supporting benign, which maps to Likely Benign.

02The sources

Evidence at a glance

Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.

gnomAD v4.1

gnomAD v2.1

Population frequency

25 / 1,205,804 alleles

gnomAD v4.1: 25 / 1,205,804 alleles. Recorded AF 2.07331e-05. Recorded homozygote count 0.

gnomAD v2.1

This variant is present in gnomAD v2.1 (AF= 0.000100952; MAF= 0.01010%, 18/178302 alleles, homozygotes = 0) and has highest observed frequency in the Admixed American population (AF= 0.000682568; MAF= 0.06826%, 18/26371 alleles, homozygotes = 0); grpmax FAF= 0.00044099.

gnomAD-Canada

Absent from gnomAD-Canada v1.0.

Applied · PM2 →

gnomAD v4.1 ↗gnomAD v2.1 ↗gnomAD-Canada ↗

SpliceAI score

0.010 maximum delta

Recorded SpliceAI maximum delta score: 0.010. Refer to the recorded PP3/BP4 rationale for interpretation.

Applied · BP4, BP7 → SpliceAI ↗

ClinVar submissions

2 reported laboratory submissions

1 Benign · 1 Likely benign.

Applied · BP6 → ClinVar ↗

No screenshot for this evidence

Functional evidence

Not recorded

No standalone functional evidence summary is recorded in evidence_summary.functional.

No listed criterion applied OncoKB ↗

Somatic evidence

No matching record reported

This variant has not previously been reported in somatic cancers (COSMIC).

Context only COSMIC ↗

For specialists

Technical detail

ACMG/AMP criteria under Not recorded, with the data and sources behind each one.

29 criteria with recorded statuses: 4 met · 5 not met · 6 not assessed · 14 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.

Pathogenic

PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 PS5

Benign

BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7

Met Not met Not assessed Not applicable

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.

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

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.

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

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

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.

Met · 4

PM2 SupportingThis 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. Details ▾Hide ▴

Evidence considered

gnomAD v2.1 AF=0.0101% (18/178
302)
gnomAD v4.1 AF=0.0021% (25/1
205
804)
Absent from gnomAD-Canada v1.0
Highest subpopulation AF: Admixed American 0.068% (v2)
0.051% (v4)

Sources

gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗

BP4 SupportingSpliceAI 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. Details ▾Hide ▴

Evidence considered

SpliceAI max delta = 0.01 (no predicted donor/acceptor gain or loss)
SpliceAI Lookup confirms no significant splice impact

Sources

spliceai ↗

BP6 SupportingThis 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. Details ▾Hide ▴

Evidence considered

ClinVar variation 2396348: Benign (Ambry Genetics
criteria provided
SCV003739622)
Likely benign (PreventionGenetics
SCV004718459)
Two independent clinical laboratories concur on benign/likely benign classification

Sources

clinvar ↗

BP7 SupportingThis 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. Details ▾Hide ▴

Evidence considered

Intronic deletion at +53 position in intron 8
SpliceAI delta = 0.01 confirms no splice impact predicted
Variant is outside conserved splice consensus region

Sources

spliceai ↗

Not met · 5 · evaluated, threshold not reached

PS4 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. Details ▾Hide ▴

Evidence considered

ClinVar variation 2396348: 2 clinical laboratory submissions (Benign
Likely benign) without case-level phenotype data

Still missing

No case counts or phenotype enrichment data available

Sources

clinvar ↗

PP3 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. Details ▾Hide ▴

Evidence considered

SpliceAI max delta = 0.01 (no predicted splice impact)
REVEL/BayesDel not applicable (not SNV)

Sources

spliceai ↗

PP5 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. Details ▾Hide ▴

Evidence considered

ClinVar variation 2396348: Benign (Ambry Genetics
criteria provided) and Likely benign (PreventionGenetics)
No expert panel or reputable source classifies as pathogenic

Sources

clinvar ↗

BA1 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. Details ▾Hide ▴

Evidence considered

gnomAD v2.1 max subpopulation AF = 0.068% (AMR)
gnomAD v4.1 max subpopulation AF = 0.051% (AMR)
Both below 1% BA1 threshold

Sources

gnomad_v2 ↗gnomad_v4 ↗

BS1 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. Details ▾Hide ▴

Evidence considered

gnomAD v2.1 max subpopulation AF = 0.068% (AMR)
gnomAD v4.1 max subpopulation AF = 0.051% (AMR)
Both below 0.3% BS1 threshold

Sources

gnomad_v2 ↗gnomad_v4 ↗

Not assessed · 6 · no assessment recorded

PS3 No functional studies have been identified that assess the biological effect of this intronic deletion. Details ▾Hide ▴

Still missing

No functional assay data available for this variant

PP1 No segregation data are available for this variant. Details ▾Hide ▴

Still missing

No family segregation data available

PP4 No patient phenotype data are available to assess specificity for a PHF6-associated disorder. Details ▾Hide ▴

Still missing

No patient phenotype information available

BS2 No specific data on observation of this variant in healthy adults are available beyond population database frequencies. Details ▾Hide ▴

Still missing

No healthy adult observation data beyond population databases

BS3 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. Details ▾Hide ▴

Still missing

No functional assay data demonstrating no deleterious effect

BS4 No segregation data are available to evaluate lack of cosegregation with disease. Details ▾Hide ▴

Still missing

No segregation data available

Not applicable · 14· recorded as not applicable Show reasons ▾Hide reasons ▴

PVS1 N/AThis 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. Details ▾Hide ▴

Evidence considered

Intronic deletion at +53 position
beyond canonical splice consensus
Variant bucket classified as 'other' by PVS1 assessment scaffold

Sources

pvs1_variant_assessmentpvs1_generic_framework ↗

PS1 N/ANo known pathogenic variant has been established at the same nucleotide change as this intronic deletion. Details ▾Hide ▴

No further detail was recorded.

PS2 N/ANo de novo data are available for this variant. Details ▾Hide ▴

No further detail was recorded.

PM1 N/AThis intronic variant is not located within a recognized functional domain or established mutational hotspot. Details ▾Hide ▴

Evidence considered

Hotspots analysis: residue_significant is false
exact variant not listed in known hotspots

PM3 N/ANo data on biallelic/in trans observations; variant is hemizygous on chromosome X. Details ▾Hide ▴

No further detail was recorded.

PM4 N/AThis is an intronic deletion that does not alter protein length; PM4 is restricted to non-repeat in-frame deletions/insertions and stop-loss variants. Details ▾Hide ▴

No further detail was recorded.

PM5 N/AThis is not a missense variant; PM5 requires a novel missense change at a residue where a different pathogenic missense change has been established. Details ▾Hide ▴

Evidence considered

PM5 candidate search: eligible_for_classic_pm5_search=false
protein consequence cannot be parsed for residue context

Sources

pm5_candidates

PM6 N/ANo de novo observation data are available for this variant. Details ▾Hide ▴

No further detail was recorded.

PP2 N/AThis is not a missense variant; PP2 applies only to missense variants in genes with a low rate of benign missense variation. Details ▾Hide ▴

No further detail was recorded.

BP1 N/AThis is not a missense variant; BP1 applies to missense variants in genes where truncation is the primary disease mechanism. Details ▾Hide ▴

No further detail was recorded.

BP2 N/ANo data on observation in trans with a pathogenic variant; variant is on chromosome X. Details ▾Hide ▴

No further detail was recorded.

BP3 N/AThis is an intronic deletion, not an in-frame indel in a repetitive coding region. Details ▾Hide ▴

No further detail was recorded.

BP5 N/ANo data available on an alternative molecular basis for disease in a proband with this variant. Details ▾Hide ▴

No further detail was recorded.

PS5 N/AClinVar classifies this variant as Benign and Likely benign. No reputable source has classified this variant as pathogenic. Details ▾Hide ▴

Evidence considered

ClinVar classification is Benign/Likely benign
no pathogenic assertion by any reputable source

Sources

clinvar ↗

Identifiers

Gene: PHF6
Transcript: NM_001015877.1
Coding (HGVS c.): NM_001015877.1:c.834+53_834+58del
Protein (HGVS p.): NP_001015877.1:p.?
GRCh38: chrX:134415168 CTTTAAA>C
GRCh37: chrX:133549198 CTTTAAA>C
ClinVar: 2396348

Gene diagram

Every interpreted variant in PHF6, mapped onto the exon structure of NM_001015877.1. Select a row to find it on the plot.

PHF6NM_001015877.1

Fetching transcript structure from UCSC…

Exons

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Transcript span

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Strand

—

Variants mapped

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Source

UCSC ncbiRefSeqCurated

All variants in PHF6 — Select a row to find it on the plot; use the link to open its page.

	Protein	Location	Classification	Link

gnomAD v4.1 25 / 1,205,804 alleles AF 2.07e-05 · 0 homozygotes · FAF 0.000347

gnomAD v2.1 18 / 178,302 alleles AF 0.000101 · 0 homozygotes · FAF 0.000441

gnomAD-Canada v1.0 Allele count data not recorded

By genetic ancestry

gnomAD v4.1

AF 2.1e-05 · 25 / 1,205,804 alleles · 0 hom · FAF 0.00035

Admixed American23 / 45,214	0.00051
African/African American1 / 57,160	1.7e-05
European (non-Finnish)1 / 893,105	1.1e-06

0 alternate alleles recorded in 7 other groups: Remaining individuals, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish.

gnomAD v2.1

AF 0.0001 · 18 / 178,302 alleles · 0 hom · FAF 0.00044

Admixed American18 / 26,371

0.00068

0 alternate alleles recorded in 7 other groups: African/African American, Ashkenazi Jewish, East Asian, European (Finnish), European (non-Finnish), Remaining individuals, South Asian.

Statements

gnomAD v4.1

This variant is present in gnomAD v4.1 (AF= 2.07331e-05; MAF= 0.00207%, 25/1205804 alleles, homozygotes = 0) and has highest observed frequency in the Admixed American population (AF= 0.000508692; MAF= 0.05087%, 23/45214 alleles, homozygotes = 0); grpmax FAF= 0.00034725.

gnomAD v2.1

gnomAD-Canada

Absent from gnomAD-Canada v1.0.

SpliceAI and Pangolin

SpliceAI acceptor lossat -128 bp

0.000

SpliceAI acceptor gainat -133 bp

0.000

SpliceAI donor lossat -48 bp

0.000

SpliceAI donor gainat +57 bp

0.010

Pangolin splice lossmagnitude shown

-0.050

Pangolin splice gain

0.000

Other predictors

REVEL: Not available
BayesDel: Not available

How the predictions were used

Evidence considered

SpliceAI max delta = 0.01 (no predicted donor/acceptor gain or loss)
SpliceAI Lookup confirms no significant splice impact

Sources

spliceai ↗

Evidence considered

Intronic deletion at +53 position in intron 8
SpliceAI delta = 0.01 confirms no splice impact predicted
Variant is outside conserved splice consensus region

Sources

spliceai ↗

Evidence considered

SpliceAI max delta = 0.01 (no predicted splice impact)
REVEL/BayesDel not applicable (not SNV)

Sources

spliceai ↗

Statement

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01).

5 paper records listed. No publication is explicitly linked to an applied criterion in the recorded metadata. None of the listed paper records explicitly indicates that the variant is named.

Recorded publications

The perspective from EASAC and FEAM on direct-to-consumer genetic testing for health-related purposes.

Fears R et al. · 2013

Position paper from EASAC and FEAM on direct-to-consumer genetic testing, reviewing scientific evidence and regulatory considerations. NM_001015877.1:c.834+53_834+58delAATTTA was not identified in this paper.
Does not name this variant
PMID 23169492 ↗
Including the initial newborn screening bloodspot collection device serial number on birth certificates: basis and recommendations from the Secretary of Health and Human Services' Advisory Committee on Heritable Disorders in Newborns and Children.

Therrell BL et al. · 2013

Recommendations from the Secretary of Health and Human Services Advisory Committee on including newborn screening bloodspot collection device serial numbers on birth certificates. NM_001015877.1:c.834+53_834+58delAATTTA was not identified in this paper.
Does not name this variant
PMID 23037933 ↗
Offering prenatal diagnostic tests: European guidelines for clinical practice [corrected].

Skirton H et al. · 2014

European clinical practice guidelines for offering prenatal diagnostic tests. NM_001015877.1:c.834+53_834+58delAATTTA was not identified in this paper.
Does not name this variant
PMID 24022298 ↗
Parental permission for pilot newborn screening research: guidelines from the NBSTRN.

Botkin JR et al. · 2014

Guidelines from the NBSTRN on parental permission for pilot newborn screening research. NM_001015877.1:c.834+53_834+58delAATTTA was not identified in this paper.
Does not name this variant
PMID 24394680 ↗
ACOG Committee Opinion No. 778 Summary: Newborn Screening and the Role of the Obstetrician-Gynecologist.

ACOG Committee Opinion on newborn screening and the role of the obstetrician-gynecologist. NM_001015877.1:c.834+53_834+58delAATTTA was not identified in this paper.
Does not name this variant
PMID 31022120 ↗

Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.

gnomAD v4.1 25 / 1,205,804 recorded alleles Open source ↗

gnomAD v2.1 Captured gnomAD v2.1 source record Open source ↗

SpliceAI Lookup Recorded maximum delta 0.010 Open source ↗

ClinVar 1 Benign · 1 Likely benign Open source ↗

COSMIC Captured COSMIC source record Open source ↗

All source links

Statements for reports

The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.

gnomAD v4.1

gnomAD v2.1

gnomAD-Canada

Absent from gnomAD-Canada v1.0.

ClinVar

This variant has been reported in ClinVar as Benign (1 clinical laboratory) and as Likely benign (1 clinical laboratory). (ClinVarID = 2396348)

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01).

Somatic

This variant has not previously been reported in somatic cancers (COSMIC).