rs587777176

chr22-20985828-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PP3_ModeratePP5

The NM_006767.4(LZTR1):c.264-13G>A variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000039 in 1,613,824 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 0.00016 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000027 ( 0 hom. )

Consequence

LZTR1
NM_006767.4 splice_polypyrimidine_tract, intron

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:11U:1

Conservation

PhyloP100: 0.0700

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PP3

Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

PP5

Variant 22-20985828-G-A is Pathogenic according to our data. Variant chr22-20985828-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 101034.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=7, Uncertain_significance=1, Pathogenic=2}. Variant chr22-20985828-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LZTR1	NM_006767.4 linkuse as main transcript	c.264-13G>A		splice_polypyrimidine_tract_variant, intron_variant		ENST00000646124.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LZTR1	ENST00000646124.2 linkuse as main transcript	c.264-13G>A		splice_polypyrimidine_tract_variant, intron_variant			NM_006767.4	P1

Frequencies

GnomAD3 genomes

AF:

0.000158

AC:

AN:

152160

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00118

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000588

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000438

AC:

AN:

251194

Hom.:

AF XY:

0.0000221

AC XY:

AN XY:

135866

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.000145

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.0000980

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000881

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000267

AC:

AN:

1461664

Hom.:

Cov.:

AF XY:

0.0000303

AC XY:

AN XY:

727148

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.000112

Gnomad4 ASJ exome

AF:

0.0000765

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.0000812

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000189

Gnomad4 OTH exome

AF:

0.0000331

GnomAD4 genome

AF:

0.000158

AC:

AN:

152160

Hom.:

Cov.:

AF XY:

0.000215

AC XY:

AN XY:

74324

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00118

Gnomad4 ASJ

AF:

0.000288

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000588

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000425

Hom.:

Bravo

AF:

0.000113

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:11Uncertain:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Pathogenic:4

Likely pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2024	LZTR1: PS3:Moderate, PS4:Moderate, PM2:Supporting, PP1, PP3 -
Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Nov 13, 2023	Non-canonical splice site variant demonstrated to result in loss of function (PMID: 24362817); Identified in patients with schwannomatosis in published literature and referred for genetic testing at GeneDx (PMID: 24362817, 31128261, 29409008); This variant is associated with the following publications: (PMID: 24362817, 31128261, 29409008, 31438995, 34426522) -
Likely pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Feb 01, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 24, 2024	This sequence change falls in intron 2 of the LZTR1 gene. It does not directly change the encoded amino acid sequence of the LZTR1 protein. This variant is present in population databases (rs587777176, gnomAD 0.02%). This variant has been observed in individuals with schwannomatosis (PMID: 24362817, 31128261, 31438995). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 101034). Studies have shown that this variant is associated with altered splicing resulting in inclusion of intronic sequence (PMID: 24362817). For these reasons, this variant has been classified as Pathogenic. -

Schwannomatosis 2

Pathogenic:4

Pathogenic, no assertion criteria provided	literature only	OMIM	Feb 01, 2014	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	Feb 21, 2024	PS3_Very Strong -
Likely pathogenic, criteria provided, single submitter	clinical testing	MGZ Medical Genetics Center	Sep 01, 2021	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Oct 23, 2023	- -

Noonan syndrome 2;C3810283:Schwannomatosis 2;C4225280:Noonan syndrome 10

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

May 20, 2022

- -

Hereditary cancer-predisposing syndrome;CN230736:Cardiovascular phenotype

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 29, 2021

The c.264-13G>A intronic pathogenic mutation results from a G to A substitution 13 nucleotides upstream from coding exon 3 in the LZTR1 gene. This alteration has been identified in multiple individuals diagnosed with schwannomatosis and has been reported to segregate with disease in one family (Piotrowski A et al. Nat. Genet., 2014 Feb;46:182-7; Louvrier C et al. Neuro-oncology, 2018 06;20:917-929; Deiller C et al. Eur J Med Genet, 2019 Aug;62:103680). In silico splice site analysis predicts that this alteration will weaken the native splice acceptor site and will result in the creation or strengthening of a novel splice acceptor site. RNA studies confirm that the predicted alternate splice acceptor site is utilized, resulting in the inclusion of 11 intronic nucleotides at the beginning of coding exon 3 and a frameshift (r.263_264ins264-11_264-1 p.K89Cfs*16) (Piotrowski A et al. Nat. Genet., 2014 Feb;46:182-7; Ambry internal data). This nucleotide position is not well conserved in available vertebrate species. Based on the supporting evidence, this variant is pathogenic for an increased risk of nerve sheath tumors and would be expected to cause autosomal recessive Noonan syndrome when present along with a second pathogenic or likely pathogenic variant on the other allele. -

RASopathy

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Dec 30, 2019

Variant summary: LZTR1 c.264-13G>A alters a nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: One predict the variant abolishes a 3' acceptor site. Five predict the variant creates a cryptic 3' acceptor site. Piotrowski et al report that this variant affects normal splicing and results in frameshift (Piotrowski_2014). Germline loss of function mutations in LZTR1 have been reported to predispose to an inherited disorder of multiple schwannomas (Piotrowski_2014). The variant allele was found at a frequency of 4.4e-05 in 251194 control chromosomes (gnomAD). As a gene with a pLI score of 0 (gnomAD) this gene is expected to be tolerant to loss of function variants. Therefore, this frequency does not allow any conclusions about variant significance in relation to Schwannomatosis.c.264-13G>A has been reported in the literature in multiple individuals affected with Schwannomatosis (Piotrowski_2014, Alaidarous_2019, Deiller_2019, Louvrier_2018). These data indicate that the variant is very likely to be associated with disease. This variant was identified in a prenatal specimen undergoing evaluation for 19 genes on a Noonan syndrome and related disorder (NSRD) test panel at our laboratory. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as likely pathogenic for the risk of multiple schwannomas and as a variant of uncertain clinical significance for the phenotype NSRD. -

Developmental disorder

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Department of Genetics, Rouen University Hospital, Normandy Center for Genomic and Personalized Medicine

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.86

Cadd

Benign

Dann

Benign

0.67

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.99

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.99

Position offset: 2

DS_AL_spliceai

0.86

Position offset: 13

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over