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 ↗

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

LZTR1 NM_006767.4

Fetching transcript structure from UCSC…

Applied criteria · 4 met · select any tile

Met

Not met

Not assessed

N/A

Strength very strong supporting

Pathogenic evidence

PVS

PS

PM

PP

Benign evidence

BA

BS

BP

—

Rationale

Select a criterion.

Sources

Evidence used

Gaps remaining

Rule

—

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