rs756485244

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 0P and 3B. BP4_ModerateBP6

The NM_006767.4(LZTR1):​c.26G>A​(p.Gly9Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000179 in 1,560,702 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000016 ( 0 hom. )

Consequence

LZTR1
NM_006767.4 missense

Scores

4
15

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:1

Conservation

PhyloP100: -0.175
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -3 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.08352724).
BP6
Variant 22-20982397-G-A is Benign according to our data. Variant chr22-20982397-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 1794905.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=2}. Variant chr22-20982397-G-A is described in Lovd as [Likely_benign].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
LZTR1NM_006767.4 linkuse as main transcriptc.26G>A p.Gly9Glu missense_variant 1/21 ENST00000646124.2 NP_006758.2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
LZTR1ENST00000646124.2 linkuse as main transcriptc.26G>A p.Gly9Glu missense_variant 1/21 NM_006767.4 ENSP00000496779 P1

Frequencies

GnomAD3 genomes
AF:
0.0000328
AC:
5
AN:
152248
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000654
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:
0.0000588
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000367
AC:
6
AN:
163374
Hom.:
0
AF XY:
0.0000571
AC XY:
5
AN XY:
87604
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000387
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.000167
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000157
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000163
AC:
23
AN:
1408454
Hom.:
0
Cov.:
32
AF XY:
0.0000244
AC XY:
17
AN XY:
695686
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.0000542
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.000161
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000461
Gnomad4 OTH exome
AF:
0.0000343
GnomAD4 genome
AF:
0.0000328
AC:
5
AN:
152248
Hom.:
0
Cov.:
33
AF XY:
0.0000538
AC XY:
4
AN XY:
74382
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.0000654
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000588
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000364
Hom.:
0
Bravo
AF:
0.00000756
ExAC
AF:
0.0000258
AC:
3

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:2Benign:1
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

LZTR1-related schwannomatosis Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingBaylor GeneticsJun 02, 2023- -
not provided Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 29, 2024This sequence change replaces glycine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 9 of the LZTR1 protein (p.Gly9Glu). This variant is present in population databases (rs756485244, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with LZTR1-related conditions. ClinVar contains an entry for this variant (Variation ID: 1794905). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on LZTR1 protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Hereditary cancer-predisposing syndrome;CN230736:Cardiovascular phenotype Benign:1
Likely benign, criteria provided, single submitterclinical testingAmbry GeneticsJan 12, 2024This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.17
BayesDel_addAF
Benign
-0.35
T
BayesDel_noAF
Benign
-0.48
CADD
Benign
18
DANN
Uncertain
0.99
DEOGEN2
Benign
0.024
T;T;.
Eigen
Benign
-0.79
Eigen_PC
Benign
-0.76
FATHMM_MKL
Benign
0.25
N
LIST_S2
Benign
0.74
.;T;T
M_CAP
Benign
0.085
D
MetaRNN
Benign
0.084
T;T;T
MetaSVM
Benign
-0.98
T
MutationAssessor
Benign
0.69
N;N;.
MutationTaster
Benign
1.0
N;N
PrimateAI
Uncertain
0.64
T
PROVEAN
Benign
-0.55
N;.;.
REVEL
Benign
0.057
Sift
Uncertain
0.0090
D;.;.
Sift4G
Uncertain
0.040
D;.;.
Polyphen
0.0080
B;B;.
Vest4
0.26
MutPred
0.39
Loss of helix (P = 3e-04);Loss of helix (P = 3e-04);Loss of helix (P = 3e-04);
MVP
0.095
MPC
1.8
ClinPred
0.18
T
GERP RS
-0.98
RBP_binding_hub_radar
0.92
RBP_regulation_power_radar
3.1
Varity_R
0.13
gMVP
0.77

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.020
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

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

Other links and lift over

dbSNP: rs756485244; hg19: chr22-21336686; API