GATA2 c.867T>C, p.Cys289=
NM_001145661.1:c.867T>C
Population Frequency
0.00143%
Low Frequency
ClinVar Classification
Likely Benign
0 publications
REVEL Score
N/A
Not Available
COSMIC Recurrence
0 occurrences
No Criteria Applied
Classification Evidence
Detailed Information
Genetic Information
Gene & Transcript Details
Gene
GATA2
Transcript
NM_001145661.2
Total Exons
7
Strand
Reverse (−)
Reference Sequence
NC_000003.11
Alternative Transcripts
| ID | Status | Details |
|---|---|---|
| NM_001145661.1 | Alternative | 7 exons | Reverse |
Variant Details
HGVS Notation
NM_001145661.1:c.867T>C
Protein Change
C289=
Location
Exon 4
(Exon 4 of 7)
5'
Exon Structure (7 total)
3'
Functional Consequence
Loss of Function
Related Variants
Variant interpretation based on transcript NM_001145661.2
Clinical Evidence
Global Frequency
0.00143%
Rare
Highest in Population
European (Finnish)
0.00405%
Rare
Global: 0.00143%
European (Finnish): 0.00405%
0%
0.0005%
0.001%
0.01%
0.05%
1%+
Allele Information
Total: 279236
Alt: 4
Homozygotes: 0
ACMG Criteria Applied
PM2
This variant is present in gnomAD (MAF= 0.00143%, 4/279236 alleles, homozygotes = 0) and at a higher frequency in the European (Finnish) population (MAF= 0.00405%, 1/24676 alleles, homozygotes = 0). The variant is rare (MAF < 0.1%), supporting PM2 criterion application.
Classification
Likely Benign
Based on 1 submitter review in ClinVar
Submitter Breakdown
Pathogenic
Likely Pathogenic
VUS
Likely Benign
Benign
Publications
0 publications
Clinical Statement
This variant has been reported in ClinVar as Likely benign (1 clinical laboratories).
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 Studies
Computational Evidence
Pathogenicity Predictions
Predictor Consensus
Mixed/VUS
PP3 Applied
No
Additional Predictors
Benign:
CADD: 1.06
VCEP Guidelines
Applied ACMG/AMP Criteria
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 (LoF) is a known mechanism of disease (e.g., nonsense, frameshift, canonical ±1 or 2 splice sites, initiation codon, single exon deletion in a LoF gene)". The evidence for this variant shows: it is a synonymous variant (C289=) that does not introduce a stop codon or disrupt splicing. Therefore, this criterion is not applied at Not Applied strength because the variant does not result in a null effect.
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: it is a synonymous change (no amino acid change) and there is no known pathogenic variant with the same amino acid alteration. Therefore, this criterion is not applied at Not Applied strength.
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 testing or parental confirmation data are available. Therefore, this criterion is not applied at Not Applied strength.
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 the gene or gene product". The evidence for this variant shows: no functional assays have been performed. Therefore, this criterion is not applied at Not Applied strength.
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 cohort data demonstrating enrichment in affected individuals. Therefore, this criterion is not applied at Not Applied strength.
PM1
PM1 (Not Applied)
Strength Modified
According to standard ACMG guidelines, the rule for PM1 is: "Located in a mutational hot spot or well-established functional domain without benign variation". The evidence for this variant shows: it is a synonymous change outside of known mutational hotspots or critical domains. Therefore, this criterion is not applied at Not Applied strength.
PM2
PM2 (Moderate)
According to standard ACMG guidelines, the rule for PM2 is: "Absent from controls (or at extremely low frequency if recessive) (Table 6) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium". The evidence for this variant shows: MAF=0.00143% in gnomAD, extremely rare (4/279236 alleles, no homozygotes). Therefore, this criterion is applied at Moderate strength because the variant is absent or at extremely low frequency in large population datasets.
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 a pathogenic allele. Therefore, this criterion is not applied at Not Applied strength.
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: it is a synonymous substitution without change in protein length. Therefore, this criterion is not applied at Not Applied strength.
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: it is synonymous and not a missense change. Therefore, this criterion is not applied at Not Applied strength.
PM6
PM6 (Not Applied)
Strength Modified
According to standard ACMG guidelines, the rule for PM6 is: "Assumed de novo, but without confirmation of paternity and maternity". The evidence for this variant shows: no de novo or parental data. Therefore, this criterion is not applied at Not Applied strength.
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 at Not Applied strength.
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 and where missense variants are a common mechanism of disease". The evidence for this variant shows: it is synonymous, not missense. Therefore, this criterion is not applied at Not Applied strength.
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 on the gene/gene product (e.g., conservation, splicing impact)". The evidence for this variant shows: CADD score 1.06 and SpliceAI 0.05 predict no deleterious effect. Therefore, this criterion is not applied at Not Applied strength.
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 data. Therefore, this criterion is not applied at Not Applied strength.
PP5
PP5 (Not Applied)
Strength Modified
According to standard ACMG guidelines, the rule for PP5 is: "Reputable source reports variant as pathogenic, but without accessible evidence". The evidence for this variant shows: sources report benign status, not pathogenic. Therefore, this criterion is not applied at Not Applied strength.
BA1
BA1 (Not Applied)
Strength Modified
According to standard ACMG guidelines, the rule for BA1 is: "Allele frequency is too high for the disorder (based on population data)". The evidence for this variant shows: MAF=0.00143%, which is below thresholds for BA1. Therefore, this criterion is not applied at Not Applied strength.
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 very low and not above expected disease threshold. Therefore, this criterion is not applied at Not Applied strength.
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 data on observation in healthy individuals. Therefore, this criterion is not applied at Not Applied strength.
BS3
BS3 (Not Applied)
Strength Modified
According to standard ACMG guidelines, the rule for BS3 is: "Well-established functional studies show no damaging effect on protein function or splicing". The evidence for this variant shows: no functional studies performed. Therefore, this criterion is not applied at Not Applied strength.
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 analysis data. Therefore, this criterion is not applied at Not Applied strength.
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: it is synonymous, not missense. Therefore, this criterion is not applied at Not Applied strength.
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 with a pathogenic variant". The evidence for this variant shows: no phase data with another variant. Therefore, this criterion is not applied at Not Applied strength.
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: it is a single-nucleotide synonymous change. Therefore, this criterion is not applied at Not Applied strength.
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 (conservation, evolutionary, splicing impact, etc.)". The evidence for this variant shows: CADD score 1.06 and SpliceAI score 0.05 predict no impact on splicing or function. Therefore, this criterion is applied at Supporting strength because in silico tools uniformly predict no deleterious effect.
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 at Not Applied strength.
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 from one clinical laboratory classifies it as Likely benign without available detailed evidence. Therefore, this criterion is applied at Supporting strength because a reputable database reports benign status.
BP7
BP7 (Supporting)
According to standard ACMG guidelines, the rule for BP7 is: "Synonymous variant with no predicted impact on splicing and the nucleotide is not highly conserved". The evidence for this variant shows: it is a synonymous change and SpliceAI predicts no splicing impact. Therefore, this criterion is applied at Supporting strength because it is a silent change with no splicing effect.