rs777243508

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PVS1PP5_Very_Strong

The NM_006767.4(LZTR1):c.1407G>A(p.Trp469*) variant causes a stop gained change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000688 in 1,612,468 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay. The gene LZTR1 is included in the ClinGen Criteria Specification Registry.

Frequency

Genomes: 𝑓 0.00017 ( 0 hom., cov: 34)

Exomes 𝑓: 0.000058 ( 0 hom. )

Consequence

LZTR1
NM_006767.4 stop_gained

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4

Conservation

PhyloP100: 7.76

Publications

3 publications found

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 Gene-Disease associations (from GenCC):

LZTR1-related schwannomatosis
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Ambry Genetics
Noonan syndrome
Inheritance: AD, AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen
schwannomatosis
Inheritance: AD Classification: DEFINITIVE Submitted by: G2P
Noonan syndrome 10
Inheritance: AR, AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Ambry Genetics
Noonan syndrome 2
Inheritance: AR Classification: STRONG, MODERATE Submitted by: Genomics England PanelApp, Ambry Genetics
breast cancer
Inheritance: AD Classification: MODERATE Submitted by: G2P
cardiofaciocutaneous syndrome
Inheritance: AD, AR Classification: NO_KNOWN Submitted by: ClinGen
Costello syndrome
Inheritance: AR, AD Classification: NO_KNOWN Submitted by: ClinGen
Noonan syndrome with multiple lentigines
Inheritance: AR, AD Classification: NO_KNOWN Submitted by: ClinGen
Noonan syndrome-like disorder with loose anagen hair
Inheritance: AR, AD Classification: NO_KNOWN Submitted by: ClinGen

LZTR1 links:

ENSG00000285314 (HGNC:):

ENSG00000285314 links:

Genome browser will be placed here

new If you want to explore the variant's impact on the transcript NM_006767.4, check out the Mutation Effect Viewer. This is especially useful for frameshift variants or if you want to visualize the effect of exon loss / intron retention.

ACMG classification

Specifications for LZTR1 are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Classification was made for transcript

Our verdict: Pathogenic. The variant received 16 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PP5

Variant 22-20993977-G-A is Pathogenic according to our data. Variant chr22-20993977-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 549753.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006767.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LZTR1	NM_006767.4	MANE Select	c.1407G>A	p.Trp469*	stop_gained	Exon 13 of 21	NP_006758.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
LZTR1	ENST00000646124.2	MANE Select	c.1407G>A	p.Trp469*	stop_gained	Exon 13 of 21	ENSP00000496779.1	Q8N653
LZTR1	ENST00000888029.1		c.1407G>A	p.Trp469*	stop_gained	Exon 13 of 21	ENSP00000558088.1
LZTR1	ENST00000888032.1		c.1404G>A	p.Trp468*	stop_gained	Exon 13 of 21	ENSP00000558091.1

Frequencies

GnomAD3 genomes

AF:

0.000171

AC:

AN:

152258

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00235

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000138

AC:

AN:

246400

AF XY:

0.000150

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000292

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00149

Gnomad NFE exome

AF:

0.00000900

Gnomad OTH exome

AF:

0.000167

GnomAD4 exome

AF:

0.0000582

AC:

AN:

1460092

Hom.:

Cov.:

AF XY:

0.0000565

AC XY:

AN XY:

726298

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33476

American (AMR)

AF:

0.0000224

AC:

AN:

44638

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26042

East Asian (EAS)

AF:

0.00

AC:

AN:

39672

South Asian (SAS)

AF:

0.00

AC:

AN:

85998

European-Finnish (FIN)

AF:

0.00156

AC:

AN:

52504

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5638

European-Non Finnish (NFE)

AF:

0.00000180

AC:

AN:

1111786

Other (OTH)

AF:

0.00

AC:

AN:

60338

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.489

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000171

AC:

AN:

152376

Hom.:

Cov.:

AF XY:

0.000282

AC XY:

AN XY:

74518

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41600

American (AMR)

AF:

0.00

AC:

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5182

South Asian (SAS)

AF:

0.00

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.00235

AC:

AN:

10628

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68036

Other (OTH)

AF:

0.00

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0000699

Hom.:

ClinVar

ClinVar submissions

Significance:Pathogenic/Likely pathogenic

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Hereditary cancer-predisposing syndrome;CN230736:Cardiovascular phenotype (1)

Noonan syndrome 2 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.57

BayesDel_noAF

Pathogenic

0.57

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

Eigen

Pathogenic

1.0

Eigen_PC

Pathogenic

0.92

FATHMM_MKL

Pathogenic

0.98

PhyloP100

7.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Mutation Taster

=1/199

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over