BRIP1c.1474-3T>CUncertain significance

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Variant interpretation report

BRIP1 c.1474-3T>C, p.?

NM_032043.3:c.1474-3T>C NP_114432.2:p.? View identifiers

Classification

Uncertain significance

Variant description:

No variant summary was recorded for this case.

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

Uncertain.The recorded classification is uncertain significance.

In plain language

Gene-level background from the recorded interpretation.

About BRIP1

No gene-level summary was recorded for this case.

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: 0 Benign evidence criteria: 1

Pathogenic criteria applied · 0

No pathogenic criterion marked as applied in the recorded assessment.

Benign criteria applied · 1

BP4Supporting

BP4 · supporting

Computational evidence supports no significant splice effect for this variant. SpliceAI predicts a maximum delta score of 0.11, which is below commonly used thresholds for a meaningful splice impact, and no additional computational result suggested a damaging effect.

Recorded classification: Uncertain significance

gene-specific framework lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback; applied criteria: BP4 supporting; combination = 1 supporting benign, which maps to VUS.

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

191 / 1,611,312 alleles

gnomAD v4.1: 191 / 1,611,312 alleles. Recorded AF 0.000118537. Recorded homozygote count 0.

gnomAD v2.1

This variant is present in gnomAD v2.1 (AF= 0.000207267; MAF= 0.02073%, 52/250884 alleles, homozygotes = 1) and has highest observed frequency in the South Asian population (AF= 0.00163431; MAF= 0.16343%, 50/30594 alleles, homozygotes = 1); grpmax FAF= 0.00127276.

No listed criterion applied

gnomAD v4.1 ↗gnomAD v2.1 ↗

No screenshot for this evidence

Computational predictions

Not recorded

No SpliceAI or REVEL score is recorded in the fields used for this tile.

Applied · BP4 →

ClinVar submissions

Not recorded

A ClinVar laboratory submission summary was not recorded.

Context only 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

Not assessed

No COSMIC evidence statement is recorded in this case.

Context only COSMIC ↗

For specialists

Technical detail

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

28 criteria with recorded statuses: 1 met · 6 not met · 13 not assessed · 8 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

Benign

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

Met Not met Not assessed Not applicable

The BRIP1 NM_032043.3:c.1474-3T>C (NP_114432.2:p.?) variant has been reported in ClinVar with predominantly benign and likely benign submissions, although uncertain significance submissions are also present.

This variant is present in population databases, including gnomAD v4.1 at an overall allele frequency of 0.01185% (191/1611312) and a highest observed South Asian frequency of 0.20440% (186/90996), with similar South Asian enrichment in gnomAD v2.1 at 0.16343% (50/30594); these values are above a 0.1% PM2 rarity threshold but below BA1 and BS1 thresholds.

In silico splice prediction does not support a significant splice effect, with a SpliceAI maximum delta score of 0.11, supporting BP4 and arguing against PP3.

Met · 1

BP4 SupportingComputational evidence supports no significant splice effect for this variant. SpliceAI predicts a maximum delta score of 0.11, which is below commonly used thresholds for a meaningful splice impact, and no additional computational result suggested a damaging effect. Details ▾Hide ▴

Evidence considered

SpliceAI max delta score 0.11
No REVEL score available
No BayesDel score available
No HCI prior available

Sources

spliceai ↗

Not met · 6 · evaluated, threshold not reached

PVS1 BRIP1 loss of function is an established disease mechanism, but this intronic variant is at the -3 position rather than the canonical +/-1,2 splice consensus, and the generic PVS1 framework does not place it in a default null-variant category. No RNA evidence was identified to show that this variant causes an abnormal transcript, so PVS1 is not applied. Details ▾Hide ▴

Evidence considered

BRIP1 generic PVS1 eligibility is supported at the gene level
Variant is non-canonical splice-region (-3) rather than +/-1
2
No variant-specific RNA evidence was identified

Still missing

RNA or minigene data for NM_032043.3:c.1474-3T>C
Direct transcript consequence for the affected splice acceptor

Sources

pvs1_gene_contextpvs1_variant_assessmentpvs1_generic_framework ↗

PM1 No evidence was identified that this intronic splice-region position lies in a well-established mutational hotspot or a critical region with little benign variation, so PM1 is not met. Details ▾Hide ▴

Evidence considered

No hotspot or critical-region evidence identified for this intronic position

PM2 This variant is present in gnomAD and does not meet a rarity threshold for PM2. In gnomAD v4.1, the highest observed population frequency is 0.20440% in South Asian individuals, which is above the 0.1% PM2 threshold; gnomAD v2.1 also shows a South Asian frequency of 0.16343%, above the same threshold. Details ▾Hide ▴

Evidence considered

gnomAD v4.1 South Asian AF 0.00204405 (186/90996)
gnomAD v2.1 South Asian AF 0.00163431 (50/30594)

Sources

gnomad_v2 ↗gnomad_v4 ↗

PP3 Available computational evidence does not support a deleterious splicing effect. SpliceAI shows a maximum delta score of 0.11, which is below commonly used concern thresholds, and no REVEL, BayesDel, or HCI prior result was available for this intronic variant. Details ▾Hide ▴

Evidence considered

SpliceAI max delta score 0.11
No REVEL score available
No BayesDel score available
No HCI prior available

Sources

spliceai ↗

BA1 This variant does not reach a stand-alone benign frequency threshold. The highest observed population frequency is 0.20440% in gnomAD v4.1 South Asian individuals, which is below the 1% BA1 threshold. Details ▾Hide ▴

Evidence considered

gnomAD v4.1 South Asian AF 0.00204405 (186/90996)

Sources

gnomad_v4 ↗

BS1 This variant does not exceed the benign strong frequency threshold. The highest observed population frequency is 0.20440% in gnomAD v4.1 South Asian individuals, which is below the 0.3% BS1 threshold. Details ▾Hide ▴

Evidence considered

gnomAD v4.1 South Asian AF 0.00204405 (186/90996)

Sources

gnomad_v4 ↗

Not assessed · 13 · no assessment recorded

PS1 PS1 applies to a different nucleotide change causing the same amino acid change. This intronic variant has no established protein consequence, and no same-protein-change comparison was identified. Details ▾Hide ▴

Evidence considered

Protein consequence remains p.?

PS2 No confirmed de novo occurrence was identified for this variant, so PS2 is not applied. Details ▾Hide ▴

Evidence considered

No de novo evidence identified in retrieved sources

Still missing

Confirmed maternity and paternity with de novo occurrence

Sources

clinvar ↗

PS3 No published functional or RNA study was identified showing a damaging effect of this exact variant on BRIP1 splicing or function, so PS3 is not applied. Details ▾Hide ▴

Evidence considered

No exact-variant functional evidence identified in retrieved sources

Still missing

Variant-specific RNA study
Variant-specific minigene or other validated functional assay

Sources

clinvar ↗

PS4 This variant has been reported in ClinVar, but no case-control enrichment or sufficient affected-individual data were identified to show that it is significantly more common in affected individuals than in controls. PS4 is not applied. Details ▾Hide ▴

Evidence considered

ClinVar submissions include benign
likely benign
and uncertain significance assertions
No enrichment dataset identified

Still missing

Exact-variant case counts
Exact-variant control comparison

Sources

clinvar ↗

PM3 No evidence was identified that this variant was observed in trans with a pathogenic variant in a recessive disease context, so PM3 is not applied. Details ▾Hide ▴

Evidence considered

No trans observation identified

Still missing

Phase data with a pathogenic variant in an appropriate recessive phenotype

PM6 No assumed de novo occurrence was identified for this variant, so PM6 is not applied. Details ▾Hide ▴

Evidence considered

No de novo evidence identified in retrieved sources

Still missing

Reported de novo occurrence without full parental confirmation

Sources

clinvar ↗

PP1 No segregation data were identified for this variant, so PP1 is not applied. Details ▾Hide ▴

Evidence considered

No cosegregation evidence identified

Still missing

Family segregation data

Sources

clinvar ↗

PP4 No highly specific phenotype or family-history evidence was identified that would support BRIP1-related disease as the sole or highly likely explanation, so PP4 is not applied. Details ▾Hide ▴

Evidence considered

No phenotype-specific case evidence identified

Still missing

Detailed phenotype and family-history data

BS2 Although this variant is present in population databases, the available data do not establish observation in a context sufficient to show that it is seen in healthy individuals at a level that excludes clinical significance for BRIP1-associated disease. BS2 is not applied. Details ▾Hide ▴

Evidence considered

Present in gnomAD v2.1 and v4.1
One homozygote in gnomAD v2.1 and none in v4.1

Still missing

Well-phenotyped unaffected observations appropriate for BRIP1-associated disease

Sources

gnomad_v2 ↗gnomad_v4 ↗

BS3 No published functional or RNA study was identified demonstrating that this exact variant has no damaging effect on BRIP1 splicing or function, so BS3 is not applied. Details ▾Hide ▴

Evidence considered

No exact-variant benign functional evidence identified

Still missing

Variant-specific benign functional or RNA evidence

Sources

clinvar ↗

BS4 No family data were identified showing lack of segregation of this variant with disease, so BS4 is not applied. Details ▾Hide ▴

Evidence considered

No nonsegregation evidence identified

Still missing

Nonsegregation data in informative families

Sources

clinvar ↗

BP2 No data were identified showing this variant in trans with a pathogenic variant for a fully penetrant dominant disorder or in cis with a pathogenic variant, so BP2 is not applied. Details ▾Hide ▴

Evidence considered

No phase evidence identified

Still missing

Phase data with another pathogenic variant

BP5 No evidence was identified for an alternative molecular basis that would explain disease independently of this variant, so BP5 is not applied. Details ▾Hide ▴

Evidence considered

No alternate molecular explanation identified

Still missing

Case-level alternate-cause evidence

Not applicable · 8· recorded as not applicable Show reasons ▾Hide reasons ▴

PM4 N/APM4 applies to protein length changes such as in-frame insertions/deletions or stop-loss variants. This is an intronic splice-region variant with no established protein length change. Details ▾Hide ▴

Evidence considered

Variant is intronic

PM5 N/APM5 applies to a novel missense change at an amino acid residue where a different pathogenic missense change has been established. This variant is intronic and does not have an established missense consequence. Details ▾Hide ▴

Evidence considered

Protein consequence remains p.?

PP2 N/APP2 is a missense criterion and is not applicable to this intronic splice-region variant. Details ▾Hide ▴

Evidence considered

Variant is intronic

PP5 N/APP5 was not applied because reputable-source assertions without independently reviewable primary evidence were not used as stand-alone pathogenic evidence. Details ▾Hide ▴

Evidence considered

No stand-alone reputable-source-only pathogenic criterion applied

BP1 N/ABP1 is a missense criterion and is not applicable to this intronic splice-region variant. Details ▾Hide ▴

Evidence considered

Variant is intronic

BP3 N/ABP3 applies to in-frame variants in repetitive regions without known function and is not applicable to this intronic splice-region variant. Details ▾Hide ▴

Evidence considered

Variant is intronic

BP6 N/ABP6 was not applied because reputable-source assertions without independently reviewable primary evidence were not used as stand-alone benign evidence. Details ▾Hide ▴

Evidence considered

No stand-alone reputable-source-only benign criterion applied

BP7 N/ABP7 is not applicable because this is not a synonymous variant, and it lies close to the splice acceptor rather than representing a silent coding change with no expected splice impact. Details ▾Hide ▴

Evidence considered

Variant is intronic at c.1474-3
Splice-region location near acceptor site

Sources

spliceai ↗

Identifiers

Gene: BRIP1
Transcript: NM_032043.3
Coding (HGVS c.): NM_032043.3:c.1474-3T>C
Protein (HGVS p.): NP_114432.2:p.?
GRCh38: chr17:61784427 A>G
GRCh37: chr17:59861788 A>G

Gene diagram

Every interpreted variant in BRIP1, mapped onto the exon structure of NM_032043.3. Select a row to find it on the plot.

BRIP1NM_032043.3

Fetching transcript structure from UCSC…

Exons

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Transcript span

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Strand

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Variants mapped

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Source

UCSC ncbiRefSeqCurated

All variants in BRIP1 — Select a row to find it on the plot; use the link to open its page.

	Protein	Location	Classification	Link

gnomAD v4.1 191 / 1,611,312 alleles AF 0.000119 · 0 homozygotes · FAF 0.0018

gnomAD v2.1 52 / 250,884 alleles AF 0.000207 · 1 homozygotes · FAF 0.00127

By genetic ancestry

gnomAD v4.1

AF 0.00012 · 191 / 1,611,312 alleles · 0 hom · FAF 0.0018

South Asian186 / 90,996	0.002
Remaining individuals4 / 62,392	6.4e-05
East Asian1 / 44,780	2.2e-05

0 alternate alleles recorded in 7 other groups: Admixed American, European (Finnish), Amish, Middle Eastern, Ashkenazi Jewish, African/African American, European (non-Finnish).

gnomAD v2.1

AF 0.00021 · 52 / 250,884 alleles · 1 hom · FAF 0.0013

South Asian50 / 30,594	0.00161 hom
Remaining individuals1 / 6,102	0.00016
European (non-Finnish)1 / 113,498	8.8e-06

0 alternate alleles recorded in 5 other groups: African/African American, Admixed American, Ashkenazi Jewish, East Asian, European (Finnish).

Statements

gnomAD v4.1

This variant is present in gnomAD v4.1 (AF= 0.000118537; MAF= 0.01185%, 191/1611312 alleles, homozygotes = 0) and has highest observed frequency in the South Asian population (AF= 0.00204405; MAF= 0.20440%, 186/90996 alleles, homozygotes = 0); grpmax FAF= 0.0018038.

gnomAD v2.1

Other predictors

REVEL: Not available
BayesDel: Not available

How the predictions were used

Evidence considered

SpliceAI max delta score 0.11
No REVEL score available
No BayesDel score available
No HCI prior available

Sources

spliceai ↗

Evidence considered

SpliceAI max delta score 0.11
No REVEL score available
No BayesDel score available
No HCI prior available

Sources

spliceai ↗

Evidence considered

Variant is intronic at c.1474-3
Splice-region location near acceptor site

Sources

spliceai ↗

Statement

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.11).

0 paper records listed. No publication is explicitly linked to an applied criterion in the recorded metadata.

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

gnomAD v4.1 191 / 1,611,312 recorded alleles Open source ↗

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

SpliceAI Lookup Captured SpliceAI source record Open source ↗

ClinVar Captured ClinVar source record 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

ClinVar

This variant has been reported in ClinVar as Likely benign (5 clinical laboratories) and as Benign (4 clinical laboratories) and as Uncertain significance (4 clinical laboratories).

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.11).

Somatic

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