Classification rationale

BP4BS1BA1BP7 Benign

LZTR1 c.2219+13C>T

The LZTR1 c.2219+13C>T (p.?) variant has been reported in ClinVar predominantly as benign, with 8 benign and 1 likely benign clinical laboratory submissions.¹ This variant is common in population databases, with gnomAD v2.1 grpmax filtering allele frequency 1.37781% and gnomAD v4.1 grpmax filtering allele frequency 1.43127%, both well above the LZTR1 benign thresholds for BS1 (0.025%) and BA1 (0.05%).² SpliceAI predicts no significant splice impact for this variant, with a maximum delta score of 0.13, which is consistent with BP4 and BP7 rather than a deleterious splicing effect.³

BP4 + BS1 + BA1 + BP7 → Benign

1 clinvar ↗

2 gnomad_v2 ↗gnomad_v4 ↗cspec ↗

3 spliceai ↗cspec ↗

LYFE Sciences is an AI system, and it can make mistakes. Criteria may be applied incorrectly, sources may be misread, and a confident-looking classification can still be wrong. Double-check every criterion and its underlying evidence before relying on any call.

Gene diagram · NM_006767.4 · variants mapped to exon structure

LZTR1 NM_006767.4

Fetching transcript structure from UCSC…

Applied criteria · 4 applied · 13 assessed

MetEvidence satisfies this criterion.

Not metEvaluated against available evidence; threshold not reached.

Not assessedApplies in principle, but no evidence was found to evaluate it.

N/ADoesn't apply to this variant type.

Applied · 4

Strength Supporting Moderate Strong Very strong

BA1 stand-alone review Benign

Population frequency is above the LZTR1 BA1 threshold. The gnomAD v2.1 grpmax filtering allele frequency is 1.37781% and the gnomAD v4.1 grpmax filtering allele frequency is 1.43127%, both above the BA1 threshold of 0.05%, supporting a benign population frequency.

gnomAD v2.1 grpmax FAF 0.0137781gnomAD v4.1 grpmax FAF 0.0143127BA1 threshold 0.05%

gnomad_v2 ↗gnomad_v4 ↗cspec ↗

BS1 strong review Benign

Population frequency is above the LZTR1 BS1 threshold. The gnomAD v2.1 grpmax filtering allele frequency is 1.37781% and the gnomAD v4.1 grpmax filtering allele frequency is 1.43127%, both above the BS1 threshold of 0.025%, supporting a benign population frequency.

gnomAD v2.1 grpmax FAF 0.0137781gnomAD v4.1 grpmax FAF 0.0143127BS1 threshold 0.025%

gnomad_v2 ↗gnomad_v4 ↗cspec ↗

BP4 supporting review Benign

SpliceAI predicts no significant splice impact for this noncanonical intronic variant (max delta score 0.13), which supports a negligible predicted splicing effect and meets the LZTR1 BP4 computational rule for splicing variants.

SpliceAI max delta score 0.13LZTR1 BP4 rule for splicing variants with negligible predicted effect

spliceai ↗cspec ↗

BP7 supporting review Benign

This variant is at a noncanonical intronic position (+13), and SpliceAI predicts no significant splice impact (max delta score 0.13). Under the LZTR1 specification, BP7 may be applied with BP4 for intronic variants outside the canonical splice site when computational evidence supports no splice effect.

Intronic position c.2219+13SpliceAI max delta score 0.13LZTR1 BP7 rule for intronic noncanonical variants used with BP4

spliceai ↗cspec ↗

Assessed · not applied · 4 not met · 9 not assessed

Pathogenic

PVS1 This variant is intronic at c.2219+13 and is not a canonical ±1,2 splice-site, nonsense, or frameshift variant.

PS2 No confirmed de novo observations were identified, so PS2 cannot be scored.

PS3 No approved LZTR1 functional study results specific to this variant were identified, so PS3 cannot be applied.

PS4 Available evidence does not show enrichment in affected individuals sufficient for the LZTR1 PS4 point thresholds (≥1 point for supporting), and the variant is common in population databases, which argues against a pathogenic case excess.

PM2 Population frequency is not below the LZTR1 PM2 supporting threshold for autosomal recessive disease.

PM3 No observations in trans with a pathogenic variant were identified, so PM3 cannot be evaluated for autosomal recessive disease.

PM6 No assumed de novo observations were identified, so PM6 cannot be scored.

PP1 No segregation data were identified, so co-segregation with disease cannot be evaluated.

PP3 Available in silico evidence does not support a deleterious splicing effect.

Benign

BS2 Although this variant is seen in homozygous state in gnomAD (21 homozygotes in v2.1 and 145 homozygotes in v4.1), unaffected clinical status and phenotype-specific evidence required for BS2 were not available, so BS2 was not independently applied.

BS4 No non-segregation data were identified, so lack of segregation in affected relatives cannot be evaluated.

BP2 No case-level data were identified showing this variant with an alternate molecular explanation in the same gene or in cis/trans with a pathogenic variant, so BP2 cannot be evaluated.

BP5 No case-level data were identified showing an alternate molecular cause of disease in a different gene, so BP5 cannot be evaluated.

N/A · 11 PS1 · PM1 · PM4 · PM5 · PP2 · PP4 · PP5 · BS3 · BP1 · BP3 · BP6

Research & evidence

Population frequency · supports benign

gnomAD v4.1

gnomAD v2.1

v4.1

This variant is present in gnomAD v4.1 (AF= 0.0124482; MAF= 1.24482%, 20042/1610034 alleles, homozygotes = 145) and has highest observed frequency in the European (non-Finnish) population (AF= 0.0144949; MAF= 1.44949%, 17089/1178968 alleles, homozygotes = 127); grpmax FAF= 0.0143127.

v2.1

This variant is present in gnomAD v2.1 (AF= 0.0100413; MAF= 1.00413%, 2808/279646 alleles, homozygotes = 21) and has highest observed frequency in the European (non-Finnish) population (AF= 0.0142263; MAF= 1.42263%, 1819/127862 alleles, homozygotes = 13); grpmax FAF= 0.0137781.

Allele frequency by ancestry

three datasets · side by side

gnomAD v4.1

1.2% · 20042 / 1,610,034
145 hom · FAF 1.4%

European (non-Finnish) 17089 / 1,178,968	1.4% 127 hom
Middle Eastern 71 / 5,662	1.3%
Admixed American 732 / 59,982	1.2% 6 hom
Remaining individuals 747 / 62,390	1.2% 2 hom
European (Finnish) 447 / 61,666	0.72% 3 hom
South Asian 641 / 91,026	0.7% 6 hom
African/African American 281 / 75,024	0.37% 1 hom
Ashkenazi Jewish 30 / 29,546	0.1%
East Asian 4 / 44,858	0.0089%

+ 1 not observed (Amish)

gnomAD v2.1

1% · 2808 / 279,646
21 hom · FAF 1.4%

European (non-Finnish) 1819 / 127,862	1.4% 13 hom
Admixed American 422 / 35,350	1.2% 5 hom
Remaining individuals 84 / 7,174	1.2%
European (Finnish) 189 / 23,624	0.8% 2 hom
South Asian 193 / 30,572	0.63% 1 hom
African/African American 85 / 24,882	0.34%
Ashkenazi Jewish 15 / 10,260	0.15%
East Asian 1 / 19,922	0.005%

gnomAD v4 ↗ gnomAD v2 ↗

ClinVar

This variant has been reported in ClinVar as Benign (8 clinical laboratories) and as Likely benign (1 clinical laboratory).

ClinVar ↗

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.13).

SpliceAI ↗

Functional No data

No calibrated functional assay or RNA evidence was identified for this variant.

OncoKB ↗

COSMIC

Somatic evidence

COSMIC

This variant has previously been reported in somatic cancers (COSMIC; COSV104394247, n = 4 times).

Hotspots

This variant does not lie in a statistically significant cancer hotspot.

COSMIC ↗

Sources & reference links

7Sources

CSpec VCEP

ClinVar

gnomAD v2.1

gnomAD v4.1

SpliceAI

OncoKB

COSMIC

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