NM_001145661.1:c.474C>T

GATA2 · NP_001139133.1:p.(Ser158=) · NM_001145661.1

GRCh37: chr3:128204967 G>A · GRCh38: chr3:128486124 G>A

Gene: GATA2 Transcript: NM_001145661.1

Final call

Likely Benign

BP4 supporting benign BP6 supporting benign BP7 supporting benign

Variant details

Gene

GATA2

Transcript

NM_001145661.1

Protein

NP_001139133.1:p.(Ser158=)

gnomAD AF

ClinVar

Likely benign

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

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).

This variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada population databases.

Two clinical testing laboratories (Ambry Genetics and Labcorp/Invitae) have independently classified this variant as Likely benign in ClinVar (VariationID 1081290).

No published study reports this exact variant; reviewed literature covers GATA2 loss-of-function disease mechanism at gene level only.

BP4 is met: computational evidence (SpliceAI, no amino acid change) suggests no impact on the gene product.

BP6 is met: the variant has been reported as Likely benign by two independent clinical laboratories.

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.

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.

Final determination: Generic ACMG/AMP 2015 fallback rules support a Likely Benign classification because either one strong benign criterion plus one supporting benign criterion, or at least two supporting benign criteria, are present.

Criteria assessment

ACMG/AMP criteria review

Criteria shown when status is available

All criteria require review: For research and educational purposes only.

Criterion	Status	Rationale	Evidence used
PVS1	N/A	Synonymous variant (p.Ser158=); does not fall into null-variant buckets (nonsense, frameshift, or canonical ±1,2 splice consensus).	pvs1_variant_assessment pvs1_gene_context
PS1	N/A	Synonymous variant does not produce a missense change; PS1 requires a different nucleotide change resulting in the same amino acid substitution as a known pathogenic variant.
PS2	Not met	No de novo data available for this variant; PS2 requires a confirmed de novo occurrence with maternity and paternity confirmed.
PS3	Not met	No functional data identified for this variant. The variant is synonymous with no predicted impact on splicing (SpliceAI max delta = 0.00), and no experimental studies have tested this variant or a systematically characterized range that includes it.	spliceai
PS4	Not met	No case-control or enrichment data demonstrating a statistically significant association of this variant with disease.
PS5	Not met	ClinVar reports Likely benign, not pathogenic; PS5 requires a pathogenic assertion from a reputable source.	clinvar
PM1	Not met	Variant does not lie in a known critical functional domain hotspot; cancerhotspots.org does not identify this residue as statistically significant, and as a synonymous variant it does not alter any residue within a characterized functional domain.
PM2	Not met	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). Absence from population databases in the absence of any other pathogenic evidence does not constitute meaningful evidence of pathogenicity for a synonymous variant.	gnomad_v2 gnomad_v4 gnomad_canada
PM3	N/A	PM3 (recessive/compound heterozygosity) is not applicable: GATA2 deficiency is autosomal dominant and no trans configuration evidence is assessed for this synonymous variant.
PM4	N/A	PM4 requires an in-frame insertion/deletion altering protein length; this is a synonymous substitution with no protein length change.
PM5	N/A	Synonymous variant (p.Ser158=); PM5 requires a different missense change at the same residue with a known pathogenic classification. No amino acid change occurs.	pm5_candidates
PM6	Not met	No de novo data available; PM6 requires a presumed de novo occurrence without confirmation of maternity and paternity.
PP1	Not met	No segregation data available for this variant.
PP2	N/A	PP2 applies to missense variants in genes with a low rate of benign missense variation; this is a synonymous variant, not a missense change.
PP3	Not met	Computational evidence supports a benign, not deleterious, interpretation: SpliceAI max delta = 0.00 (no splicing impact); no REVEL, BayesDel, or HCI prior scores are available.	spliceai
PP4	Not met	No patient phenotype or clinical data available for this variant.
PP5	Not met	ClinVar classification is Likely benign (2 clinical laboratories, single submitter review status), not pathogenic; PP5 requires a pathogenic assertion from a reputable source.	clinvar
BA1	Not met	Variant is absent from gnomAD; allele frequency is 0%, which does not exceed the BA1 threshold of >1%.	gnomad_v2 gnomad_v4
BS1	Not met	Variant is absent from gnomAD; allele frequency is 0%, which does not exceed the BS1 threshold of >0.3%.	gnomad_v2 gnomad_v4
BS2	Not met	No data on observation of this variant in healthy adults for a fully penetrant disorder.
BS3	Not met	No functional studies demonstrating no deleterious effect of this variant. The synonymous nature and zero SpliceAI score are consistent with a benign effect, but these are computational predictions, not experimental functional data as required by BS3.	spliceai
BS4	Not met	No segregation data available demonstrating lack of cosegregation with disease.
BP1	N/A	BP1 is specific to missense variants in genes where primarily truncating variants cause disease; this is a synonymous variant, not a missense change.
BP2	Not met	No evidence of this variant observed in trans with a pathogenic variant in GATA2.
BP3	N/A	BP3 applies to variants in repeat regions or involving repeat length; this is a single-nucleotide substitution outside a repeat region.
BP4	Met	Computational evidence suggests 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, and no in silico tool predicts a deleterious effect.	spliceai
BP5	Not met	No evidence of an alternative molecular basis for disease in this case.
BP6	Met	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
BP7	Met	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.	spliceai

Disclaimer: The content and results provided by LYFE Sciences are for research and educational purposes only and must not be used as a substitute for professional medical judgment, diagnosis, or treatment. Always consult a qualified healthcare professional before making any clinical decisions.