BRIP1 c.1473+14del, p.?
NM_032043.3:c.1473+14del
Likely Benign
This deep intronic deletion in BRIP1 shows no predicted impact on splicing or protein function (BP4), is reported as benign by a reputable source (BP6), and is extremely rare in controls (PM2). The conflicting moderate pathogenic and supporting benign evidence results in classification as Variant of Uncertain Significance.
ACMG/AMP Criteria Applied
PM2
BP4
BP6
Genetic Information
Gene & Transcript Details
Gene
BRIP1
Transcript
NM_032043.3
MANE Select
Total Exons
20
Strand
Reverse (−)
Reference Sequence
NC_000017.10
Alternative Transcripts
| ID | Status | Details |
|---|---|---|
| NM_032043.2 | RefSeq Select | 20 exons | Reverse |
| NM_032043.1 | Alternative | 20 exons | Reverse |
Variant Details
HGVS Notation
NM_032043.3:c.1473+14del
Protein Change
?
Location
Exon 10
(Exon 10 of 20)
5'Exon Structure (20 total)3'
Functional Consequence
Loss of Function
Related Variants
Variant interpretation based on transcript NM_032043.3
Genome Browser
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HGVS InputNM_032043:c.1473+14del
Active Tracks
ConservationRefSeqClinVargnomAD
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Clinical Data
Global Frequency
0.000864%
Very Rare
Highest in Population
South Asian
0.00706%
Rare
Global: 0.000864%
South Asian: 0.00706%
0%
0.05%
0.1%
1%
5%
10%+
Allele Information
Total: 231502Alt: 2Homozygotes: 0
ACMG Criteria Applied
PM2
This variant is present in gnomAD (MAF= 0.000864%, 2/231502 alleles, homozygotes = 0) and at a higher frequency in the South Asian population (MAF= 0.00706%, 2/28340 alleles, homozygotes = 0). The variant is rare (MAF < 0.1%), supporting PM2 criterion application.
Classification
Benign
Based on 1 submitter review in ClinVar
Submitter Breakdown
1 B
Pathogenic
Likely Path.
VUS
Likely Benign
Benign
Publications (0)
No publication details.
Clinical Statement
This variant has been reported in ClinVar as Benign (1 clinical laboratories).
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
Mixed/VUS
PP3 Applied
No
Additional Predictors
Benign:
CADD: -0.28
VCEP Guidelines
Applied ACMG/AMP Criteria (VCEP Specific)
PVS1
PVS1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PVS1 is: 'Null variant in a gene where loss of function is a known mechanism of disease'. The evidence for this variant shows: 'It is a single-nucleotide deletion 14 base pairs into an intron, outside canonical splice sites, and does not create a stop codon or frameshift in the coding sequence'. Therefore, this criterion is not applied because the variant is not a null variant in a canonical location.
PS1
PS1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PS1 is: 'Same amino acid change as a known pathogenic variant but different nucleotide change'. The evidence for this variant shows: 'No amino acid change is generated as the variant is intronic'. Therefore, this criterion is not applied.
PS2
PS2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PS2 is: 'De novo (both maternity and paternity confirmed) in a patient with the disease and no family history'. The evidence for this variant shows: 'No de novo inheritance data are available'. Therefore, this criterion is not applied.
PS3
PS3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PS3 is: 'Well-established functional studies supportive of a damaging effect on gene or gene product'. The evidence for this variant shows: 'No functional studies have been performed'. Therefore, this criterion is not applied.
PS4
PS4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PS4 is: 'Prevalence in affected individuals significantly increased compared with controls'. The evidence for this variant shows: 'No case‐control or segregation data demonstrating enrichment 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: 'Located in a mutational hotspot or well-established functional domain without benign variation'. The evidence for this variant shows: 'This is an intronic variant outside known functional domains or hotspots'. Therefore, this criterion is not applied.
PM2
PM2 (Moderate)
According to standard ACMG guidelines, the rule for PM2 is: 'Absent from controls (or at extremely low frequency if recessive)'. The evidence for this variant shows: 'MAF=0.000864% in gnomAD (2/231,502 alleles) and no homozygotes'. Therefore, this criterion is applied at Moderate strength because the allele frequency is below the threshold for rarity.
PM3
PM3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM3 is: 'Detected in trans with a pathogenic variant for recessive disorders'. The evidence for this variant shows: 'No data on trans configuration with pathogenic variants'. Therefore, this criterion is not applied.
PM4
PM4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM4 is: 'Protein length changes due to in-frame deletions/insertions or stop-loss variants'. The evidence for this variant shows: 'The variant is intronic and does not alter the protein length'. Therefore, this criterion is not applied.
PM5
PM5 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM5 is: 'Novel missense change at an amino acid residue where a different pathogenic missense change has been seen'. The evidence for this variant shows: 'No missense change is produced'. Therefore, this criterion is not applied.
PM6
PM6 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM6 is: 'Assumed de novo, without confirmation of paternity and maternity'. The evidence for this variant shows: 'No parental data available'. Therefore, this criterion is not applied.
PP1
PP1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP1 is: 'Co-segregation with disease in multiple affected family members'. The evidence for this variant shows: 'No family segregation data'. Therefore, this criterion is not applied.
PP2
PP2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP2 is: 'Missense variant in a gene with a low rate of benign missense variation where missense is a common mechanism of disease'. The evidence for this variant shows: 'This is an intronic variant, not missense'. Therefore, this criterion is not applied.
PP3
PP3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP3 is: 'Multiple lines of computational evidence support a deleterious effect'. The evidence for this variant shows: 'In silico predictors including SpliceAI (0.01) and CADD (-0.28) indicate no deleterious impact'. Therefore, this criterion is not applied.
PP4
PP4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP4 is: 'Patient’s phenotype or family history highly specific for a disease with a single genetic etiology'. The evidence for this variant shows: 'No patient phenotype or family history provided'. Therefore, this criterion is not applied.
PP5
PP5 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP5 is: 'Reputable source reports variant as pathogenic, without accessible evidence'. The evidence for this variant shows: 'No reputable source reports this variant as pathogenic'. Therefore, this criterion is not applied.
BA1
BA1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BA1 is: 'Allele frequency is too high for the disorder'. The evidence for this variant shows: 'MAF=0.000864% which is below thresholds for common benign variants'. Therefore, this criterion is not applied.
BS1
BS1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BS1 is: 'Allele frequency is greater than expected for the disorder'. The evidence for this variant shows: 'MAF is low and not greater than expected'. Therefore, this criterion is not applied.
BS2
BS2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BS2 is: 'Observed in healthy individuals with full penetrance expected at an early age'. The evidence for this variant shows: 'No phenotypic data on individuals in population databases'. Therefore, this criterion is not applied.
BS3
BS3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BS3 is: 'Well-established functional studies show no damaging effect'. The evidence for this variant shows: 'No functional assay data available'. Therefore, this criterion is not applied.
BS4
BS4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BS4 is: 'Lack of segregation in affected family members'. The evidence for this variant shows: 'No segregation data'. Therefore, this criterion is not applied.
BP1
BP1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP1 is: 'Missense variant in a gene where only LoF causes disease'. The evidence for this variant shows: 'The variant is intronic'. Therefore, this criterion is not applied.
BP2
BP2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP2 is: 'Observed in trans with a pathogenic variant for dominant disorders or in cis for recessive disorders'. The evidence for this variant shows: 'No data on cis/trans configuration'. Therefore, this criterion is not applied.
BP3
BP3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP3 is: 'In-frame deletions/insertions in a repetitive region without known function'. The evidence for this variant shows: 'This is a single-nucleotide deletion in an intron, not a repetitive region'. Therefore, this criterion is not applied.
BP4
BP4 (Supporting)
According to standard ACMG guidelines, the rule for BP4 is: 'Multiple lines of computational evidence suggest no impact on gene or gene product'. The evidence for this variant shows: 'SpliceAI score 0.01 and CADD -0.28 indicate no splicing or deleterious effect'. Therefore, this criterion is applied at Supporting strength because computational predictions consistently indicate no impact.
BP5
BP5 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP5 is: 'Variant found in a case with an alternate molecular basis for disease'. The evidence for this variant shows: 'No case reports with alternate molecular diagnoses'. Therefore, this criterion is not applied.
BP6
BP6 (Supporting)
According to standard ACMG guidelines, the rule for BP6 is: 'Reputable source reports variant as benign, but without accessible evidence'. The evidence for this variant shows: 'ClinVar entry by one clinical laboratory classifies it as Benign'. Therefore, this criterion is applied at Supporting strength because a reputable source reports a benign classification without primary data.
BP7
BP7 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP7 is: 'Synonymous variant with no predicted impact on splicing'. The evidence for this variant shows: 'This is an intronic deletion, not a synonymous exonic variant'. Therefore, this criterion is not applied.