NM_001145661.1:c.474C>T (p.Ser158=) is a synonymous variant in GATA2 with no predicted impact on splicing (SpliceAI max delta = 0.00).1 This variant is absent from gnomAD v2.1 and v4.1 population databases.2 Two clinical testing laboratories (Ambry Genetics and Labcorp/Invitae) have independently classified this variant as Likely benign in ClinVar (VariationID 1081290).3 Multiple lines of computational evidence (BP4) support a benign interpretation: SpliceAI predicts no splicing impact, and the variant does not alter the amino acid sequence.4 BP7 is met: this is a synonymous variant for which splicing prediction algorithms predict no impact on the splice consensus sequence nor the creation of a new splice site.5 Three supporting benign criteria are met (BP4, BP6, BP7). Under generic ACMG/AMP 2015 combination rules, two supporting benign criteria are sufficient for a Likely Benign classification.6
GATA2
Final classification
Likely Benign
GATA2 c.474C>T · p.Ser158=
GATA2
NM_001145661.1:c.474C>T (p.Ser158=) is a synonymous variant in GATA2 with no predicted impact on splicing (SpliceAI max delta = 0.00).
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 benign, BP6 supporting benign, BP7 supporting benign; combination = 3 supporting benign, which maps to Likely Benign.
Classification rationale
BP4BP6BP7
Likely Benign
GATA2 c.474C>T
BP4 + BP6 + BP7
→
Likely Benign
6
generic_acmg_combination_rules
Gene diagram
· NM_001145661.1 · variants mapped to exon structure
GATA2
NM_001145661.1
Fetching transcript structure from UCSC…
Applied criteria · 3 applied · 17 assessed
Applied · 3
Strength
Supporting
Moderate
Strong
Very strong
✓
BP4
supporting
Benign
Multiple lines of computational evidence suggest no impact on the gene product. SpliceAI predicts no splicing impact (max delta score = 0.00). The variant is synonymous with no amino acid change. No in silico tool predicts a deleterious effect.
SpliceAI max delta score = 0.00no predicted impact on any splice site (acceptor gainacceptor loss
✓
BP6
supporting
Benign
Two clinical testing laboratories (Ambry Genetics and Labcorp/Invitae) have classified this variant as Likely benign in ClinVar (VariationID 1081290). Although review status is 'criteria provided, single submitter' and not 3-star expert panel, two independent clinical laboratory submissions provide reproducible benign evidence.
ClinVar VariationID 1081290: Likely benign.Two submissions: Ambry Genetics (SCV006531223) and Labcorp/Invitae (SCV001598983)both Likely benign.
✓
BP7
supporting
Benign
Synonymous variant (p.Ser158=) for which SpliceAI predicts no impact on splicing (max delta score = 0.00; no predicted acceptor gain, acceptor loss, donor gain, or donor loss). The nucleotide position is not predicted to affect the splice consensus sequence or create a novel splice site.
Variant is synonymous: NP_001139133.1:p.(Ser158=).SpliceAI max delta score = 0.00all individual delta scores (acceptor gain
Assessed · not applied
Pathogenic
PS2
No de novo data available for this variant; PS2 requires confirmed de novo occurrence (with maternity and paternity confirmed).
PS3
No functional data identified for this variant.
PS4
No case-control or enrichment data demonstrating a statistically significant association of this variant with disease.
PM1
Variant does not lie in a known critical functional domain hotspot.
PM2
Variant is absent from gnomAD v2.1 and v4.1; however, this is a synonymous variant with no predicted functional impact (SpliceAI max delta = 0.00, no REVEL/BayesDel scores).
PM6
No de novo data available; PM6 requires a confirmed de novo occurrence without confirmation of maternity and paternity.
PP1
No segregation data available for this variant.
PP3
Multiple in silico tools predict no deleterious effect.
PP4
No patient phenotype or clinical data available for this variant.
PP5
ClinVar classification is Likely benign (2 clinical laboratories, single submitter review status), not pathogenic.
Benign
BA1
Variant is absent from gnomAD; allele frequency is 0%, which does not exceed the BA1 threshold of >1%.
BS1
Variant is absent from gnomAD; allele frequency is 0%, which does not exceed the BS1 threshold of >0.3%.
BS2
No data on observation of this variant in healthy adults for a fully penetrant disorder.
BS3
No functional studies demonstrating no deleterious effect of this variant.
BS4
No segregation data available demonstrating lack of cosegregation with disease.
BP2
No evidence of this variant observed in trans with a pathogenic variant in GATA2.
BP5
No evidence of an alternative molecular basis for disease in this case.
N/A · 5
PVS1 · PS1 · PM5 · PP2 · BP1
Research & evidence
Population frequency · supports benign
gnomAD v4.1
gnomAD v2.1
v4.1
Absent from gnomAD v4.1.
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
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
gnomAD v2.1
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
gnomAD Canada 🇨🇦
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
ClinVar
This variant has been reported in ClinVar as Likely benign (2 clinical laboratories). (ClinVarID = 1081290)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00).
Functional
Unknown Oncogenic Effect
OncoKB identified curated literature and non-variant-specific oncogenicity context for review; listed oncogenicity label: Unknown Oncogenic Effect.
COSMIC
Cancer hotspots
Somatic evidence
Not in COSMIC / hotspots
COSMIC
This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).
Hotspots
This variant does not lie in a statistically significant hotspot.
Sources & reference links
Triaged references · 6 PMIDs not cited in assessment
25626707 ↗
Whole-genome sequencing in newborn screening? A statement on the continued importance of targeted approaches in newborn screening programmes.
CLINVAR
22947299 ↗
Specific guidelines for assessing and improving the methodological quality of economic evaluations of newborn screening.
CLINVAR
23037933 ↗
Including the initial newborn screening bloodspot collection device serial number on birth certificates: basis and recommendations from the Secretary of Health and Human Services' Advisory Committee on Heritable Disorders in Newborns and Children.
CLINVAR
24022298 ↗
Offering prenatal diagnostic tests: European guidelines for clinical practice [corrected].
CLINVAR
28492532 ↗
Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.
CLINVAR