PTEN c.164+29A>G, p.?
NM_000314.8:c.164+29A>G
Variant of Uncertain Significance (VUS)
This intronic variant at +29 has a population frequency exceeding the VCEP BA1 threshold, with computational tools and splicing predictors indicating no impact. BA1 Stand Alone and BP4/BP7 supportive benign evidence lead to a final classification of Benign.
ACMG/AMP Criteria Applied
BA1
BP4
BP7
Genetic Information
Gene & Transcript Details
Gene
PTEN
Transcript
NM_000314.8
MANE Select
Total Exons
9
Strand
Forward (+)
Reference Sequence
NC_000010.10
Alternative Transcripts
| ID | Status | Details |
|---|---|---|
| NM_000314.7 | RefSeq Select | 9 exons | Forward |
| NM_000314.5 | Alternative | 9 exons | Forward |
| NM_000314.4 | Alternative | 9 exons | Forward |
| NM_000314.3 | Alternative | 9 exons | Forward |
| NM_000314.6 | Alternative | 9 exons | Forward |
Variant Details
HGVS Notation
NM_000314.8:c.164+29A>G
Protein Change
?
Location
Exon 2
(Exon 2 of 9)
5'Exon Structure (9 total)3'
Functional Consequence
Loss of Function
Related Variants
Variant interpretation based on transcript NM_000314.8
Genome Browser
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HGVS InputNM_000314:c.164+29A>G
Active Tracks
ConservationRefSeqClinVargnomAD
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Clinical Data
Global Frequency
0.00178%
Rare
Highest in Population
European (non-Finnish)
0.00389%
Rare
Global: 0.00178%
European (non-Finnish): 0.00389%
0%
0.05%
0.1%
1%
5%
10%+
Allele Information
Total: 281262Alt: 5Homozygotes: 0
ACMG Criteria Applied
PM2
This variant is present in gnomAD (MAF= 0.00178%, 5/281262 alleles, homozygotes = 0) and at a higher frequency in the European (non-Finnish) population (MAF= 0.00389%, 5/128440 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
Functional Summary
The PTEN 164+29a>G variant has not been functionally characterized, and its biological significance remains unknown.
Database Previews
OncoKB
JAX-CKB
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Computational Analysis
Pathogenicity Predictions
Predictor Consensus
Mixed/VUS
PP3 Applied
No
Additional Predictors
Benign:
CADD: 1.42
VCEP Guidelines
Applied ACMG/AMP Criteria (VCEP Specific) VCEP Guidelines
PVS1
PVS1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PVS1 is: 'Null variant (nonsense, frameshift, start codon, splicing +1/2, startgain, single or multi-exon deletion) in a gene where loss of function is a known mechanism of disease.' The evidence for this variant shows: it is an intronic change at +29 not predicted to disrupt coding sequence or canonical splice sites. Therefore, this criterion is not applied because the variant does not create a null allele.
PS1
PS1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PS1 is: 'Same amino acid change as a previously established pathogenic variant regardless of nucleotide change OR different variant at same nucleotide position as a pathogenic splicing variant, where in silico models predict impact equal to or greater than the known pathogenic variant.' The evidence for this variant shows: no amino acid change and no known pathogenic variant at this intronic position. Therefore, PS1 is not applied.
PS2
PS2 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PS2 is: 'Strong: De novo (both maternity and paternity confirmed) observation in a patient with the disease and no family history.' The evidence for this variant shows: no de novo data are available. Therefore, PS2 is not applied.
PS3
PS3 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PS3 is: 'Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product. RNA, mini-gene, or other assay shows impact on splicing.' The evidence for this variant shows: no functional or splicing assays have been performed. Therefore, PS3 is not applied.
PS4
PS4 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PS4 is: 'Strong: Probands with specificity score 4-15.5 OR the prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls.' The evidence for this variant shows: no case-level or prevalence data in affected individuals. Therefore, PS4 is not applied.
PM1
PM1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PM1 is: 'Located in a mutational hot spot and/or critical and well-established functional domain. Defined to include residues in catalytic motifs: 90-94, 123-130, 166-168 (NP_000305.3).' The evidence for this variant shows: it lies at intronic position +29, outside defined catalytic motifs. Therefore, PM1 is not applied.
PM2
PM2 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PM2 is: 'Supporting: Absent in population databases or present at <0.00001 (0.001%) allele frequency in gnomAD.' The evidence for this variant shows: MAF = 0.00178 (0.178%), which exceeds the threshold. Therefore, PM2 is not applied.
PM3
PM3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM3 is: 'For recessive disorders, detected in trans with a pathogenic variant in a patient with the disease.' The evidence for this variant shows: no data regarding trans configuration with a pathogenic PTEN variant. Therefore, PM3 is not applied.
PM4
PM4 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PM4 is: 'Moderate: Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.' The evidence for this variant shows: it is intronic with no effect on protein length. Therefore, PM4 is not applied.
PM5
PM5 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PM5 is: 'Moderate: Missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.' The evidence for this variant shows: it does not change an amino acid. Therefore, PM5 is not applied.
PM6
PM6 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PM6 is: 'Moderate: Assumed de novo, but without confirmation of paternity and maternity.' The evidence for this variant shows: no de novo or familial data. Therefore, PM6 is not applied.
PP1
PP1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PP1 is: 'Supporting: Co-segregation with disease in multiple affected family members, with 3 or 4 meioses observed.' The evidence for this variant shows: no segregation data. Therefore, PP1 is not applied.
PP2
PP2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP2 is: 'Supporting: Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.' The evidence for this variant shows: it is intronic. Therefore, PP2 is not applied.
PP3
PP3 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PP3 is: 'Supporting: Multiple lines of computational evidence support a deleterious effect on the gene or gene product. Splicing variants: Concordance of SpliceAI and VarSeak.' The evidence for this variant shows: SpliceAI predicts minimal impact (max 0.02). Therefore, PP3 is not applied.
PP4
PP4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP4 is: 'Supporting: Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.' The evidence for this variant shows: no phenotype data provided. Therefore, PP4 is not applied.
PP5
PP5 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP5 is: 'Supporting: A reputable source reports the variant as pathogenic.' The evidence for this variant shows: not found in ClinVar or other expert databases. Therefore, PP5 is not applied.
BA1
BA1 (Stand Alone) Strength Modified
According to VCEP guidelines, the rule for BA1 is: 'gnomAD Filtering allele frequency >0.00056 (0.056%).' The evidence for this variant shows: MAF = 0.00178 (0.178%), which exceeds the threshold. Therefore, BA1 is applied at Stand Alone strength.
BS1
BS1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BS1 is: 'Strong: gnomAD Filtering allele frequency from 0.000043 (0.0043%) up to 0.00056 (0.056%).' The evidence for this variant shows: MAF = 0.00178 (0.178%), which exceeds the upper limit. Therefore, BS1 is not applied.
BS2
BS2 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BS2 is: 'Strong: Observed in the homozygous state in a healthy or PHTS-unaffected individual.' The evidence for this variant shows: no homozygous observations reported. Therefore, BS2 is not applied.
BS3
BS3 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BS3 is: 'Strong: Well-established in vitro or in vivo functional studies shows no damaging effect on protein function; for intronic variants, an RNA assay demonstrating no splicing impact.' The evidence for this variant shows: no functional or splicing assays performed. Therefore, BS3 is not applied.
BS4
BS4 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BS4 is: 'Strong: Lack of segregation in affected members of two or more families.' The evidence for this variant shows: no segregation data. Therefore, BS4 is not applied.
BP1
BP1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP1 is: 'Supporting: Missense variant in a gene for which primarily truncating variants cause disease.' The evidence for this variant shows: it is intronic. Therefore, BP1 is not applied.
BP2
BP2 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BP2 is: 'Supporting: Observed in trans with a pathogenic PTEN variant OR at least three observations in cis with different pathogenic PTEN variants.' The evidence for this variant shows: no phase or cis/trans data available. Therefore, BP2 is not applied.
BP3
BP3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP3 is: 'Supporting: In-frame indel in a repetitive region without a known function.' The evidence for this variant shows: not an indel. Therefore, BP3 is not applied.
BP4
BP4 (Supporting)
According to VCEP guidelines, the rule for BP4 is: 'Supporting: Multiple lines of computational evidence suggest no impact on gene or gene product. Splicing variants: Concordance of SpliceAI and VarSeak; Missense variants: REVEL scores < 0.5.' The evidence for this variant shows: SpliceAI maximum score 0.02 and CADD score 1.42, indicating no impact. Therefore, BP4 is applied at Supporting strength.
BP5
BP5 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BP5 is: 'Supporting: Variant found in a case with an alternate molecular basis for disease.' The evidence for this variant shows: no case reports with an alternate molecular basis. Therefore, BP5 is not applied.
BP6
BP6 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP6 is: 'Supporting: A reputable source reports the variant as benign.' The evidence for this variant shows: not reported as benign by expert sources. Therefore, BP6 is not applied.
BP7
BP7 (Supporting)
According to VCEP guidelines, the rule for BP7 is: 'Supporting: A synonymous (silent) or intronic variant at or beyond +7/-21 for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice.' The evidence for this variant shows: intronic position +29 and SpliceAI max score 0.02. Therefore, BP7 is applied at Supporting strength.