22-20982334-T-A

Position:

• chr22-20982334-T-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 1P and 1B. PP5 BP4

The NM_006767.4(LZTR1):​c.-38T>A variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000295 in 1,493,790 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000031 (0 hom.)
• Consequence: LZTR1 NM_006767.4 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:4 U:2
• Conservation: PhyloP100: -0.226

Genes affected

LZTR1 (HGNC:6742): (leucine zipper like post translational regulator 1) This gene encodes a member of the BTB-kelch superfamily. Initially described as a putative transcriptional regulator based on weak homology to members of the basic leucine zipper-like family, the encoded protein subsequently has been shown to localize exclusively to the Golgi network where it may help stabilize the Gogli complex. Deletion of this gene may be associated with DiGeorge syndrome. [provided by RefSeq, Jul 2008]

LZTR1 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PP5: Variant 22-20982334-T-A is Pathogenic according to our data. Variant chr22-20982334-T-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 549752.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=2, Pathogenic=1, Likely_pathogenic=3}.
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.75). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LZTR1	NM_006767.4	c.-38T>A		5_prime_UTR_premature_start_codon_gain_variant	1/21	ENST00000646124.2	NP_006758.2
LZTR1	NM_006767.4	c.-38T>A		5_prime_UTR_variant	1/21	ENST00000646124.2	NP_006758.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LZTR1	ENST00000646124	c.-38T>A		5_prime_UTR_premature_start_codon_gain_variant	1/21		NM_006767.4	ENSP00000496779.1
LZTR1	ENST00000646124	c.-38T>A		5_prime_UTR_variant	1/21		NM_006767.4	ENSP00000496779.1

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152126 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00000802 AC: 1 AN: 124616 Hom.: 0 AF XY: 0.0000147 AC XY: 1 AN XY: 67828

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000214

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000313 AC: 42 AN: 1341664 Hom.: 0 Cov.: 29 AF XY: 0.0000242 AC XY: 16 AN XY: 660042

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000393

Gnomad4 OTH exome AF: 0.0000180

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152126 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 74314

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.0000340

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:4 Uncertain:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

May 26, 2022

Published functional studies demonstrate an approximately 20% reduction in activity compared to the wildtype. Additionally, models suggest that the variant creates a new ATG start site upstream of the endogenous start site but this was not tested functionally (Pagnamenta et al., 2019); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 30859559) -

Noonan syndrome 2;C4225280:Noonan syndrome 10 Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein

Apr 07, 2021

ACMG classification criteria: PS4 supporting, PM2, PM3 strong -

Noonan syndrome 2 Pathogenic:1

Pathogenic, criteria provided, single submitter

research

Genomic Medicine Theme, NIHR Oxford Biomedical Research Centre, University of Oxford

Jan 30, 2019

As well as lying in trans with a pathogenic allele and co-segregating with disease in the pedigree, the effect of the 5’-UTR variant c.-38T>A on the expression of LZTR1 was further investigated using a dual luciferase reporter assay, as previously described (Calvo et al 2009 PMID: 19372376). The ratio of renilla to firefly luciferase was consistently reduced to 77-85% for the mutant 5’-UTR in comparison to the WT. -

Noonan syndrome 2;C3810283:LZTR1-related schwannomatosis;C4225280:Noonan syndrome 10 Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Feb 02, 2022

- -

LZTR1-related schwannomatosis Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Baylor Genetics

Jul 23, 2023

- -

Hereditary cancer-predisposing syndrome;CN230736:Cardiovascular phenotype Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 12, 2023

The c.-38T>A variant is located in the 5' untranslated region (5’ UTR) of the LZTR1 gene. This variant results from a T to A substitution 38 bases upstream from the first translated codon and introduces a possible alternative, out-of-frame initiation codon. This alteration has been detected in trans with LZTR1 c.1311G>A p.W437* in two siblings with suspected autosomal recessive Noonan Syndrome; an unaffected sibling did not carry both variants (Pagnamenta AT et al. Clin. Genet., 2019 Jun;95:693-703). An in vitro functional assay indicated that this variant results in a partial reduction in protein expression; however, the clinical relevance of the observed level of reduction is unclear (Pagnamenta AT et al. Clin. Genet., 2019 Jun;95:693-703). This nucleotide position is not well conserved in available vertebrate species. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.75
CADD	Benign	11
DANN	Benign	0.77
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1459786357; hg19: chr22-21336623;