Back
LYFE SCIENCES
Project: HERA
NM_007294.4:c.4327C>G
p.Arg1443Gly  ·  BRCA1
Starting
Initialising…
0%
Legacy Engine
Ready
View Legacy →
Classification rationale
1

The BRCA1 c.4327C>G (p.Arg1443Gly; p.R1443G) variant has been reported in ClinVar, where the aggregate classification is Benign with expert panel review.

clinvar ↗
2

This variant is present in population databases, including gnomAD v2.1 at 9/282760 alleles (AF 3.18291e-05; grpmax FAF 2.294e-05) and gnomAD v4.1 at 65/1613954 alleles (AF 4.02738e-05; grpmax FAF 3.666e-05), which exceeds the BRCA1 BS1 supporting threshold of 0.00002 but remains below the BA1 threshold of 0.001.

gnomad_v2 ↗ gnomad_v4 ↗ cspec ↗
3

In two calibrated functional studies curated by ENIGMA, this variant showed no functional impact and protein behavior similar to benign control variants, supporting BS3 at strong strength.

4

Computational evidence does not support a damaging effect: SpliceAI predicts no significant splice impact with a maximum delta score of 0.01, BayesDel no-AF is -0.285466, and REVEL is 0.007; because Arg1443 lies outside the BRCA1 ENIGMA clinically important functional domains, this profile supports BP1_Strong rather than PP3.

spliceai ↗ cspec ↗
Applied criteria
Met
Not met
Not assessed
N/A
Very strong
Strong
Moderate
Supporting
Pathogenic evidence
PVS
PVS1
PS
PS1
PS2
PS3
PS4
PM
PM1
PM2
PM3
PM4
PM5
PM6
PP
PP1
PP2
PP3
PP4
PP5
Benign evidence
BA
BA1
BS
BS1
BS2
BS3
BS4
BP
BP1
BP2
BP3
BP4
BP5
BP6
BP7
PVS1
—
—
Rationale
Select a criterion to inspect its explanation.
Evidence used
  • —
Gaps remaining
  • —
Rule
—
Publications
—
Research and evidence
gnomAD v2.1 evidence
v2.1
gnomAD v4.1 evidence
v4.1
01
Population
gnomAD v2.1This variant is present in gnomAD v2.1 (AF= 3.18291e-05; MAF= 0.00318%, 9/282760 alleles, homozygotes = 0) and has highest observed frequency in the Remaining individuals population (AF= 0.000138581; MAF= 0.01386%, 1/7216 alleles, homozygotes = 0); grpmax FAF= 2.294e-05.
gnomAD v4.1This variant is present in gnomAD v4.1 (AF= 4.02738e-05; MAF= 0.00403%, 65/1613954 alleles, homozygotes = 0) and has highest observed frequency in the Admixed American population (AF= 8.33528e-05; MAF= 0.00834%, 5/59986 alleles, homozygotes = 0); grpmax FAF= 3.666e-05.
gnomAD v2 ↗ gnomAD v4 ↗
ClinVar evidence
02
ClinVar
This variant has been reported in ClinVar as Likely benign (8 clinical laboratories) and as Benign (6 clinical laboratories) and as Uncertain significance (3 clinical laboratories) and as Benign by Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) (expert panel).
ClinVar ↗
Functional evidence
03
Functional
OncoKB: Likely Neutral
OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Likely Neutral; curated oncogenicity label: Likely Neutral.
OncoKB ↗
In silico evidence
04
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). REVEL score = 0.007. BayesDel score = -0.285466.
SpliceAI ↗
COSMIC evidence
05
COSMIC
This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).
COSMIC ↗
Cancer hotspots evidence
06
Cancer hotspots Not found
This variant does not lie in a statistically significant hotspot.
ResidueR1443
Hotspots ↗