Variant classification summary

NM_002529.3:c.655G>A

NTRK1 · NP_002520.2:p.(Gly219Arg) · NM_002529.3

GRCh37: chr1:156838377 G>A · GRCh38: chr1:156868585 G>A

Gene: NTRK1 Transcript: NM_002529.3

Final call

VUS

PM2 supporting BP4 supporting

Variant details

Gene

NTRK1

Transcript

NM_002529.3

Protein

NP_002520.2:p.(Gly219Arg)

gnomAD AF

6.441207236825154e-07 (v4.1)

ClinVar

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

PM2 (Supporting): absent from gnomAD v2.1 and present only once in gnomAD v4.1 (AF 6.4e-07; 1/1,552,504 alleles; 0 homozygotes), an extremely rare population frequency.

2

BP4 (Supporting): REVEL 0.217 falls at or below the <=0.290 benign-supporting threshold (ClinGen SVI calibration, PMID 36413997).

3

Overall classification VUS: the single supporting pathogenic criterion (PM2) and single supporting benign criterion (BP4) constitute conflicting evidence satisfying no ACMG/AMP 2015 combination rule.

Final determination: Generic ACMG/AMP 2015 combination rules require thresholds (e.g. PVS1+PM, 2 PS, 3 PM, etc. for pathogenic; BA1, 2 BS, or 1 BS+1 BP for benign) that are not met by a single supporting pathogenic criterion (PM2) plus a single supporting benign criterion (BP4); this conflicting/insufficient combination defaults to Uncertain Significance.

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	Not applicable: this is a missense substitution (p.Gly219Arg), so no null-variant mechanism such as nonsense-mediated decay is triggered.	pvs1_generic_framework generic_acmg_combination_rules
PS1	Not assessed	Not assessed: no pathogenic variant producing the identical amino-acid change (p.Gly219Arg) was available for comparison.
PS2	Not assessed	Not assessed: no proband de novo occurrence is documented - no parental testing or maternity/paternity confirmation was available.
PS3	Not assessed	Not assessed: no published functional or biochemical assay evidence for p.Gly219Arg was available.
PS4	Not assessed	Not assessed: no affected-case counts, control counts, or variant-specific case series were available.
PM1	Not assessed	Not assessed: insufficient evidence was available to determine whether the variant lies in a critical functional domain or mutational hotspot.
PM2	Met	Met (supporting): absent from gnomAD v2.1 and present only once in gnomAD v4.1 (AF 6.4e-07; 1/1,552,504 alleles; 0 homozygotes), an extremely rare population frequency.	gnomad_v2 gnomad_v4 gnomad_canada
PM3	Not assessed	Not assessed: no affected proband observations, pathogenic second allele, or phasing/inheritance data were available.
PM4	N/A	Not applicable: the variant is a missense substitution, so no change in protein length occurs.	pvs1_generic_framework generic_acmg_combination_rules
PM5	Not assessed	Not assessed: no pathogenic missense variant at the same codon (p.Gly219) was available for comparison.
PM6	Not assessed	Not assessed: no suspected de novo occurrence without confirmed parentage is documented.
PP1	Not assessed	Not assessed: no affected or unaffected relatives, informative meioses, or co-segregation data were available.
PP2	Not assessed	Not assessed: insufficient evidence was available to apply this criterion.
PP3	Not met	Not met: REVEL 0.217 falls below the >=0.644 pathogenic-supporting threshold (SpliceAI max delta 0.168 also below 0.2).	revel spliceai
PP4	Not assessed	Not assessed: no patient phenotype, family history, or diagnostic indication was available.
PP5	Not assessed	Not assessed: no ClinVar expert-panel assertion of Pathogenic or Likely pathogenic exists for this exact variant.	clinvar
BA1	Not met	Not met: gnomAD v4.1 allele frequency 6.4e-07 is far below the >5% stand-alone benign threshold.	gnomad_v2 gnomad_v4 generic_acmg_combination_rules
BS1	Not met	Not met: the gnomAD v4.1 allele frequency of 6.4e-07 is far below the population frequency expected for a benign variant in this disease.	gnomad_v2 gnomad_v4
BS2	Not met	Not met: no homozygotes were observed in gnomAD (0 in v2.1 and v4.1), providing no unaffected homozygous adult to support a benign effect.	gnomad_v2 gnomad_v4
BS3	Not assessed	Not assessed: no functional assay evidence of normal wild-type activity for p.Gly219Arg was available.
BS4	Not assessed	Not assessed: no affected relatives tested for the variant or reliable non-segregation observations were available.
BP1	Not assessed	Not assessed: insufficient evidence was available to apply this criterion.
BP2	Not assessed	Not assessed: no data show the variant in cis with a pathogenic variant or in trans with a benign variant.
BP3	N/A	Not applicable: the variant is a missense substitution, not an in-frame insertion/deletion in a repetitive region.	pvs1_generic_framework generic_acmg_combination_rules
BP4	Met	Met (supporting): REVEL 0.217 falls at or below the <=0.290 benign-supporting threshold (ClinGen SVI calibration, PMID 36413997).	revel spliceai
BP5	Not assessed	Not assessed: no patient case with an alternative molecular basis for the disease was available.
BP6	Not assessed	Not assessed: no ClinVar expert-panel assertion of Benign or Likely benign exists for this exact variant.	clinvar
BP7	N/A	Not applicable: the variant is a missense substitution, not a synonymous variant.	generic_acmg_combination_rules

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.