Analysis in progress

Initialising…

complete

This report is still being assembled — sections appear as each stage finishes. It isn't final yet.

GNA11

Final classification

Likely Pathogenic

GNA11 c.735+1_736-1del · p.?

GNA11

Gene

GNA11

Transcript

NM_002067.5

HGVS · transcript:coding

NM_002067.5:c.735+1_736-1del

Consequence

N/A

GRCh38

chr19:3119051 GAGGTGGGCCCTGCCCTGAGCAGGGGCAGCGTTGGGGGCCGGGCCTTCCCCACCTGCCAAGCCTGGGTCCCCTCACCTGGGTCCCCCCAGCTGCCCCTTGGGCTGTGTGCAGTGGGGAGGGCCCCTCTGATTCCCTCTGCCTTCGCTCCCGCC>G

GRCh37

chr19:3119049 GAGGTGGGCCCTGCCCTGAGCAGGGGCAGCGTTGGGGGCCGGGCCTTCCCCACCTGCCAAGCCTGGGTCCCCTCACCTGGGTCCCCCCAGCTGCCCCTTGGGCTGTGTGCAGTGGGGAGGGCCCCTCTGATTCCCTCTGCCTTCGCTCCCGCC>G

Basis gene-specific framework lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback; applied criteria: PVS1 very strong, PM2 moderate; combination = 1 very strong + 1 moderate, which maps to Likely Pathogenic. ▾

gene-specific framework lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback; applied criteria: PVS1 very strong, PM2 moderate; combination = 1 very strong + 1 moderate, which maps to Likely Pathogenic.

Classification rationale

PVS1PM2 Likely Pathogenic

GNA11 c.735+1_736-1del

NM_002067.5:c.735+1_736-1del is a canonical splice site deletion removing the donor (+1) and acceptor (-1) sites of intron 5 of GNA11, qualifying for PVS1 at very strong strength under ClinGen SVI PVS1 recommendations (PMC6185798), with GNA11 loss of function established as a germline disease mechanism.¹ The variant is absent from gnomAD v2.1 and is observed at an extremely low frequency in gnomAD v4.1 (AF = 1.24e-06, 2/1,613,802 alleles, 0 homozygotes), meeting PM2 at moderate strength.² Per generic ACMG/AMP 2015 combination rules (Richards et al., PMID:25741868), one Very Strong criterion (PVS1) plus one Moderate criterion (PM2) yields a classification of Likely Pathogenic.³

PVS1 + PM2 → Likely Pathogenic

1 pvs1_generic_framework ↗gnomad_v4 ↗spliceai ↗

2 gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗

3 generic_acmg_combination_rules

Gene diagram · NM_002067.5 · variants mapped to exon structure

GNA11 NM_002067.5

Fetching transcript structure from UCSC…

Applied criteria · 2 met · select any tile

Met

Not met

Not assessed

N/A

Strength very strong supporting

Pathogenic evidence

PVS

Benign evidence

—

Rationale

Select a criterion.

Sources

Evidence used

Gaps remaining

Rule

—

Research & evidence

Population frequency · supports pathogenic

gnomAD v4.1

gnomAD v2.1

v4.1

This variant is present in gnomAD v4.1 (AF= 1.23931e-06; MAF= 0.00012%, 2/1613802 alleles, homozygotes = 0) and has highest observed frequency in the Remaining individuals population (AF= 1.6001e-05; MAF= 0.00160%, 1/62496 alleles, homozygotes = 0).

v2.1

Absent from gnomAD v2.1.

🇨🇦 CA

Absent from gnomAD-Canada v1.0.

Allele frequency by ancestry

three datasets · side by side

gnomAD v4.1

0.00012% · 2 / 1,613,802
0 hom

Remaining individuals 1 / 62,496	0.0016%
South Asian 1 / 91,082	0.0011%

+ 8 not observed (Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, Ashkenazi Jewish, African/African American, European (non-Finnish))

gnomAD v2.1

Absent · 0 / ?
0 hom

Not observed in any ancestry group.

gnomAD Canada 🇨🇦

Absent · 0 / ?
0 hom

Not observed in any ancestry group.

gnomAD v4 ↗ gnomAD v2 ↗ gnomAD 🇨🇦 ↗

ClinVar

This variant is absent from ClinVar.

ClinVar ↗

In silico

SpliceAI predicts possible splice impact for this variant (max delta score = 1.00).

SpliceAI ↗

Functional No data

No calibrated functional assay or RNA evidence was identified for this variant.

OncoKB ↗

COSMIC

Somatic evidence

COSMIC

This variant has previously been reported in somatic cancers (COSMIC; COSV107230858, n = 1 times).

Hotspots

This variant does not lie in a statistically significant cancer hotspot.

COSMIC ↗

Sources & reference links

7Sources

ClinVar

gnomAD v2.1

gnomAD v4.1

gnomAD-Canada

SpliceAI

OncoKB

COSMIC