NTRK1

Final classification

VUS

NTRK1 c.926C>T · p.Pro309Leu

NTRK1

NM_002529.3:c.926C>T (p.Pro309Leu) in NTRK1 is classified as a Variant of Uncertain Significance (VUS) under the generic ACMG/AMP 2015 framework.

Gene

NTRK1

Transcript

NM_002529.3

HGVS · transcript:coding

NM_002529.3:c.926C>T

Consequence

N/A

GRCh38

chr1:156873708 C>T

GRCh37

chr1:156843500 C>T

Basis gene-specific framework lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback; applied criteria: PM2 supporting; combination = 1 supporting, which maps to VUS. ▾

gene-specific framework lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback; applied criteria: PM2 supporting; combination = 1 supporting, which maps to VUS.

Classification rationale

PM2 VUS

NTRK1 c.926C>T

NM_002529.3:c.926C>T (p.Pro309Leu) in NTRK1 is classified as a Variant of Uncertain Significance (VUS) under the generic ACMG/AMP 2015 framework.¹ One supporting pathogenic criterion was met: PM2 (absent from gnomAD v2.1 and v4.1 population databases).² No benign criteria were met. Population absence does not support BA1 (>1%), BS1 (>0.3%), or BS2 (no homozygotes observed). In silico predictions are mixed (REVEL 0.554 damaging; BayesDel 0.172 neutral; SpliceAI 0.00 no splice effect), preventing application of either PP3 or BP4.³ Only one supporting-level criterion (PM2) was met, which is insufficient to reach Likely Pathogenic or Likely Benign under the ACMG/AMP 2015 combination rules. The variant remains as Uncertain Significance.⁴

PM2 → VUS

1 generic_acmg_combination_rules

2 gnomad_v2 ↗gnomad_v4 ↗

3 revelbayesdelspliceai ↗

4 generic_acmg_combination_rules

Gene diagram · NM_002529.3 · variants mapped to exon structure

NTRK1 NM_002529.3

Fetching transcript structure from UCSC…

Applied criteria · 1 applied · 16 assessed

Applied · 1

Strength Supporting Moderate Strong Very strong

✓

PM2 supporting Pathogenic

NM_002529.3:c.926C>T is absent from gnomAD v2.1 (0/246,210 alleles) and gnomAD v4.1 (0 alleles). Under generic ACMG/AMP rules, absence from population databases at an allele frequency below 0.1% supports PM2 at supporting strength for a missense variant without additional corroborating evidence.

gnomAD v2.1: 0/246210 alleles (AF=0.000%)gnomAD v4.1: absent

gnomad_v2 ↗gnomad_v4 ↗

Assessed · not applied

Pathogenic

PS1 PS1 requires the same amino acid change (Pro309Leu) to have been previously established as pathogenic.

PS3 No functional studies have been performed on NM_002529.3:c.926C>T (p.Pro309Leu).

PS4 No case-level evidence was identified for this variant.

PM1 PM1 requires location in a mutational hotspot or well-established critical functional domain without benign variation.

PM5 PM5 requires a different pathogenic missense change at the same amino acid residue (Pro309).

PP2 PP2 requires a low rate of benign missense variation in the gene with missense variants being a common disease mechanism.

PP3 PP3 requires multiple lines of computational evidence supporting a deleterious effect.

PP5 PP5 requires a reputable source to have recently reported the variant as pathogenic, with the evidence not available for independent review.

Benign

BA1 BA1 requires allele frequency >1% in population databases.

BS1 BS1 requires allele frequency >0.3% in population databases.

BS2 BS2 requires observation in a healthy adult in a homozygous or hemizygous state (or in trans with a pathogenic variant for dominant disorders).

BS3 BS3 requires well-established functional studies showing no damaging effect on protein function or splicing.

BP1 BP1 applies when a missense variant occurs in a gene for which only truncating variants are known to cause disease.

BP2 BP2 requires observation in trans with a pathogenic variant for a fully penetrant dominant disorder, or in cis with a pathogenic variant for a recessive disorder.

BP4 BP4 requires multiple lines of computational evidence to suggest no impact on the gene or gene product.

BP6 BP6 requires a reputable source to report the variant as benign with evidence not available for independent review.

N/A · 8 PVS1 · PS2 · PM6 · PP1 · PP4 · BS4 · BP5 · BP7

Research & evidence

Population frequency

gnomAD v4.1

gnomAD v2.1

v4.1

Absent from gnomAD v4.1.

v2.1

This variant is present in gnomAD v2.1 (AF= 0; MAF= 0.00000%, 0/246210 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 0; MAF= 0.00000%, 0/15518 alleles, homozygotes = 0).

🇨🇦 CA

Absent from gnomAD-Canada v1.0.

Allele frequency by ancestry

three datasets · side by side

gnomAD v4.1

Absent · 0 / ?
0 hom

Not observed in any ancestry group.

gnomAD v2.1

Absent · 0 / 246,210
0 hom

Not observed in any ancestry group.

+ 8 not observed (African/African American, Admixed American, Ashkenazi Jewish, East Asian, European (Finnish), European (non-Finnish), Remaining individuals, South Asian)

gnomAD Canada 🇨🇦

Absent · 0 / ?
0 hom

Not observed in any ancestry group.

gnomAD v4 ↗ gnomAD v2 ↗ gnomAD 🇨🇦 ↗

ClinVar

This variant has been reported in ClinVar as Uncertain significance (1 clinical laboratory). (ClinVarID = 526728)

ClinVar ↗

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.554. BayesDel score = 0.172357.

SpliceAI ↗

Functional Unknown Oncogenic Effect

OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. NTRK1, a receptor tyrosine kinase, is altered by gene fusions in various cancer types.

OncoKB ↗

COSMIC

Cancer hotspots

Somatic evidence Not in COSMIC / hotspots

COSMIC

This variant does not lie in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV62323938, n = 1 times).

Hotspots

This variant does not lie in a statistically significant hotspot.

COSMIC ↗ Hotspots ↗

Sources & reference links

8Sources

ClinVar

gnomAD v2.1

gnomAD v4.1

gnomAD-Canada

SpliceAI

OncoKB

COSMIC

Cancer hotspots

Triaged references · 2 PMIDs not cited in assessment

20301726 ↗ NTRK1 Congenital Insensitivity to Pain with Anhidrosis. CLINVAR

29419974 ↗ Congenital Insensitivity to Pain Overview. CLINVAR