NM_004119.2:c.2246C>A

FLT3 · NP_004110.2:p.(Ser749Ter) · NM_004119.2

GRCh37: chr13:28599042 G>T · GRCh38: chr13:28024905 G>T

Gene: FLT3 Transcript: NM_004119.2

Final call

VUS

PVS1 very strong PM2 supporting

Variant details

Gene

FLT3

Transcript

NM_004119.2

Protein

NP_004110.2:p.(Ser749Ter)

gnomAD AF

ClinVar

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

NM_004119.2:c.2246C>A (p.Ser749Ter) is a nonsense variant in exon 18 of 24 in FLT3. The variant is predicted to undergo nonsense-mediated decay, and germline FLT3 loss of function is associated with autoimmune thyroid disease risk (PVS1_VeryStrong met).

The variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada, meeting PM2 at supporting strength.

No additional pathogenic or benign criteria are met. PVS1_VeryStrong plus PM2_Supporting does not reach the threshold for Likely Pathogenic (requires PVS1_VeryStrong plus at least two Supporting or one Moderate criterion). The variant is classified as a Variant of Uncertain Significance.

The local FLT3 ITD framework criteria (PM1, PM5, PS3, PM4, BP3) are designed for in-frame internal tandem duplications and activating length mutations and do not apply to this nonsense substitution variant.

Final determination: The local FLT3 framework Likely Pathogenic rules require PVS1_VeryStrong plus either 1 Moderate or 2 Supporting criteria; with only 1 Supporting (PM2) met, the combination does not reach any Pathogenic or Likely Pathogenic threshold.

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	Met	NM_004119.2:c.2246C>A is a nonsense variant (p.Ser749Ter) in exon 18 of 24. The predicted transcript is expected to undergo nonsense-mediated decay. Germline FLT3 loss-of-function is associated with autoimmune thyroid disease risk (PMID:32581359), satisfying the PVS1 gene-level gate. Under PMC6185798, nonsense variants upstream of the last exon in genes with an established LoF disease mechanism qualify for PVS1 at very strong strength.	pvs1_generic_framework pvs1_variant_assessment pvs1_gene_context
PS1	N/A	PS1 requires the same amino acid change to have been previously classified pathogenic. This is a nonsense variant with no prior ClinVar entry for any variant at this position.	clinvar
PS2	Not met	No de novo data are available for this variant.
PS3	Not met	No variant-specific functional data exist for NM_004119.2:c.2246C>A (p.Ser749Ter). The OncoKB entry for S749* lists 'Unknown Oncogenic Effect' and provides no functional annotation. The local FLT3 framework PS3 rule is specific to in-frame ITDs and activating length mutations with OncoKB gain-of-function support, and does not apply to this nonsense variant. No experimental functional studies were identified in the literature.	oncokb
PS4	Not met	No case-control or cohort data are available for this variant. The variant is absent from ClinVar and COSMIC.	clinvar
PS5	N/A	PS5 applies when a different nucleotide change at the same position results in the same amino acid change and has been classified pathogenic. This is a nonsense variant with no other pathogenic nucleotide change at c.2246.
PM1	Not met	The local FLT3 framework PM1 is specific to in-frame ITDs and activating length mutations in the juxtamembrane hotspot (codons 589-599) and does not cover nonsense variants. Under generic ACMG/AMP, PM1 requires location in a mutational hotspot or critical functional domain without benign variation. While p.Ser749Ter lies within the tyrosine kinase domain (aa 604-953), cancerhotspots.org identifies no statistically significant hotspot at this residue, and applying domain-level PM1 to a truncating variant would partially overlap with the PVS1 loss-of-function rationale.	vcep_flt3_itd_hotspot_and_function
PM2	Met	NM_004119.2:c.2246C>A is absent from all population databases including gnomAD v2.1, v4.1, and gnomAD-Canada, supporting a pathogenic role under PM2 at supporting strength.	gnomad_v2 gnomad_v4 gnomad_canada
PM5	Not met	The local FLT3 framework PM5 is specific to novel in-frame ITDs and activating length mutations in the juxtamembrane hotspot class and does not apply to this nonsense variant. Under generic ACMG/AMP, PM5 requires a different pathogenic missense variant at the same residue. No pathogenic or likely pathogenic variant at codon S749 is present in ClinVar, and this variant is a nonsense change rather than a missense.	pm5_candidates clinvar vcep_flt3_itd_hotspot_and_function
PM6	Not met	No de novo data are available for this variant, and no confirmed maternity/paternity testing has been reported.
PP1	Not met	No segregation data are available for this variant.
PP2	Not met	HCI Prior score is not available for FLT3, and no gene-specific constraint data support PP2.
PP3	Not met	SpliceAI predicts no significant splice impact (max delta score 0.07, below the 0.1 threshold). BayesDel score is 0.257, which is below commonly used pathogenic thresholds. REVEL score is not available. Multiple lines of computational evidence do not support a deleterious effect on splicing, and this nonsense variant's pathogenicity is mediated through protein truncation rather than missense-level computational features.	spliceai bayesdel
PP4	Not met	No phenotype or clinical data are available for individuals carrying this variant.
PP5	Not met	This variant is absent from ClinVar and has not been classified by any expert panel or reputable source.	clinvar
BA1	Not met	This variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada. The allele frequency does not exceed the 1% threshold for BA1.	gnomad_v2 gnomad_v4 gnomad_canada
BS1	Not met	This variant is absent from gnomAD and does not exceed the 0.3% threshold for BS1.	gnomad_v2 gnomad_v4
BS2	Not met	No homozygous observations are reported for this variant in gnomAD.	gnomad_v2 gnomad_v4
BS3	Not met	No functional studies demonstrating no deleterious effect are available for this variant.
BS4	Not met	No segregation data are available to demonstrate lack of cosegregation with disease.
BP1	Not met	BP1 applies to missense variants where a truncating mechanism is known to cause disease. This variant is itself a nonsense (truncating) variant, so BP1 does not apply.
BP2	Not met	No observation of this variant in trans with a known pathogenic FLT3 variant has been reported.
BP4	Not met	While SpliceAI (max delta 0.07) and BayesDel (0.257) predict no significant impact on splicing or protein function, BP4 is not applicable to nonsense variants whose primary disease mechanism is through protein truncation and NMD rather than through splicing effects or missense-level computational features.	spliceai bayesdel
BP5	Not met	No observation of this variant in cis with a known pathogenic variant has been reported.
BP6	Not met	This variant is absent from ClinVar and has not been classified as benign by any reputable source.	clinvar
BP7	N/A	BP7 applies to silent variants or intronic variants outside splice sites. This is a nonsense (stop-gain) variant, not a synonymous or intronic change.

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