NM_006767.4:c.2219+13C>T

LZTR1 · NP_006758.2:p.? · NM_006767.4

GRCh37: chr22:21350414 C>T · GRCh38: chr22:20996125 C>T

Gene: LZTR1 Transcript: NM_006767.4

Final call

Benign

BP4 supporting BS1 strong BA1 stand-alone benign BP7 supporting

Variant details

Gene

LZTR1

Transcript

NM_006767.4

Protein

NP_006758.2:p.?

gnomAD AF

ClinVar

OncoKB

Classification rationale

Interpretation summary

Generated evidence synthesis

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.

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%).

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.

Final determination: Rule17 in the ClinGen RASopathy Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for LZTR1 Version 1.3.0 v1.3.0 criteria-combination framework is satisfied by the adjudicated criteria, so the variant is classified as Benign.

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
BP4	Met	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 cspec
BP6	N/A	BP6 is not used in this LZTR1 specification.	cspec
PP1	Not assessed	No segregation data were identified, so co-segregation with disease cannot be evaluated.	cspec
BS1	Met	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 gnomad_v4 cspec
PM6	Not assessed	No assumed de novo observations were identified, so PM6 cannot be scored.	cspec
PVS1	Not met	This variant is intronic at c.2219+13 and is not a canonical ±1,2 splice-site, nonsense, or frameshift variant. The variant-level PVS1 assessment therefore does not place it in a default loss-of-function PVS1 category, so PVS1 is not met.	cspec pvs1_gene_context pvs1_variant_assessment vcep_lztr1_classification_flowchart_page_1
BS4	Not assessed	No non-segregation data were identified, so lack of segregation in affected relatives cannot be evaluated.	cspec
BS3	N/A	BS3 is not used in this LZTR1 specification.	cspec
PM5	N/A	This variant does not create an amino acid substitution, so same-codon pathogenic missense comparisons cannot be applied.	cspec
PS4	Not met	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.	cspec gnomad_v2 gnomad_v4 clinvar
BP3	N/A	BP3 is not used in this LZTR1 specification.	cspec
BA1	Met	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 gnomad_v4 cspec
BP2	Not assessed	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.	cspec
BP5	Not assessed	No case-level data were identified showing an alternate molecular cause of disease in a different gene, so BP5 cannot be evaluated.	cspec
PS3	Not assessed	No approved LZTR1 functional study results specific to this variant were identified, so PS3 cannot be applied.	cspec vcep_svi_rasopathy_vcep_v2_approved_functional_studies
PM4	N/A	This intronic variant does not change protein length and is not an in-frame insertion, in-frame deletion, or stop-loss variant.	cspec
PS1	N/A	This variant does not define a known amino acid substitution, so PS1 cannot be applied.	cspec
PS2	Not assessed	No confirmed de novo observations were identified, so PS2 cannot be scored.	cspec
PP3	Not met	Available in silico evidence does not support a deleterious splicing effect. SpliceAI predicts no significant splice impact with a maximum delta score of 0.13, so the predicted outcome does not support PP3.	spliceai cspec
PM3	Not assessed	No observations in trans with a pathogenic variant were identified, so PM3 cannot be evaluated for autosomal recessive disease.	cspec vcep_lztr1_classification_flowchart_page_1
PP5	N/A	PP5 is not used in this LZTR1 specification.	cspec
PP2	N/A	PP2 is not used in this LZTR1 specification.	cspec
PM2	Not met	Population frequency is not below the LZTR1 PM2 supporting threshold for autosomal recessive disease. The gnomAD v2.1 grpmax filtering allele frequency is 1.37781% and the gnomAD v4.1 grpmax filtering allele frequency is 1.43127%, both far above the PM2 threshold of 0.0025%, so PM2 is not met.	gnomad_v2 gnomad_v4 cspec
PP4	N/A	PP4 is not used in this LZTR1 specification because the phenotype is genetically heterogeneous.	cspec
BP7	Met	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.	spliceai cspec
PM1	N/A	PM1 is not used in this LZTR1 specification.	cspec
BS2	Not assessed	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.	gnomad_v2 gnomad_v4 cspec
BP1	N/A	BP1 is not used in this LZTR1 specification.	cspec

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