rs750582696

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 0P and 1B. BP4

The NM_006767.4(LZTR1):​c.1982G>A​(p.Gly661Glu) variant causes a missense change. The variant allele was found at a frequency of 0.0000167 in 1,613,492 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 Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000017 ( 0 hom. )

Consequence

LZTR1
NM_006767.4 missense

Scores

9
10

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:5

Conservation

PhyloP100: 6.87
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 -1 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.33994466).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
LZTR1NM_006767.4 linkc.1982G>A p.Gly661Glu missense_variant 17/21 ENST00000646124.2 NP_006758.2 Q8N653A0A384NL67

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
LZTR1ENST00000646124.2 linkc.1982G>A p.Gly661Glu missense_variant 17/21 NM_006767.4 ENSP00000496779.1 Q8N653

Frequencies

GnomAD3 genomes
AF:
0.0000131
AC:
2
AN:
152148
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000241
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:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000147
Gnomad OTH
AF:
0.00
GnomAD4 exome
AF:
0.0000171
AC:
25
AN:
1461344
Hom.:
0
Cov.:
32
AF XY:
0.0000206
AC XY:
15
AN XY:
726968
show subpopulations
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:
0.0000116
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000198
Gnomad4 OTH exome
AF:
0.0000331
GnomAD4 genome
AF:
0.0000131
AC:
2
AN:
152148
Hom.:
0
Cov.:
32
AF XY:
0.00
AC XY:
0
AN XY:
74300
show subpopulations
Gnomad4 AFR
AF:
0.0000241
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000147
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.0000113
ExAC
AF:
0.00000824
AC:
1
EpiCase
AF:
0.0000545
EpiControl
AF:
0.00

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:5
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Noonan syndrome 10 Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingCenter For Human Genetics And Laboratory Diagnostics, Dr. Klein, Dr. Rost And ColleaguesApr 11, 2017- -
not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingWomen's Health and Genetics/Laboratory Corporation of America, LabCorpJun 06, 2024Variant summary: LZTR1 c.1982G>A (p.Gly661Glu) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 1.7e-05 in 1613492 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in LZTR1 causing autosomal recessive Noonan Syndrome 2 (1.7e-05 vs 0.0032), allowing no conclusion about variant significance for LZTR1-related conditions. To our knowledge, no occurrence of c.1982G>A in individuals affected with LZTR1-related conditions and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 448963). Based on the evidence outlined above, the variant was classified as uncertain significance. -
LZTR1-related schwannomatosis Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingBaylor GeneticsJan 27, 2024- -
not provided Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpDec 29, 2023This sequence change replaces glycine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 661 of the LZTR1 protein (p.Gly661Glu). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. 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: 448963). 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) performed at Invitae indicates that this missense variant is not expected to disrupt LZTR1 protein function with a negative predictive value of 80%. 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 Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsOct 05, 2023The p.G661E variant (also known as c.1982G>A), located in coding exon 17 of the LZTR1 gene, results from a G to A substitution at nucleotide position 1982. The glycine at codon 661 is replaced by glutamic acid, an amino acid with similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. 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
AlphaMissense
Uncertain
0.41
BayesDel_addAF
Uncertain
0.13
D
BayesDel_noAF
Uncertain
-0.050
CADD
Uncertain
25
DANN
Uncertain
0.99
DEOGEN2
Benign
0.095
T;T
Eigen
Benign
0.021
Eigen_PC
Uncertain
0.23
FATHMM_MKL
Uncertain
0.93
D
LIST_S2
Uncertain
0.93
.;D
M_CAP
Benign
0.041
D
MetaRNN
Benign
0.34
T;T
MetaSVM
Benign
-0.89
T
MutationAssessor
Benign
0.85
L;L
PrimateAI
Uncertain
0.78
T
PROVEAN
Benign
-0.68
N;.
REVEL
Uncertain
0.33
Sift
Benign
0.24
T;.
Sift4G
Benign
0.33
T;.
Polyphen
0.15
B;B
Vest4
0.59
MutPred
0.41
Loss of catalytic residue at G661 (P = 0.0132);Loss of catalytic residue at G661 (P = 0.0132);
MVP
0.13
MPC
0.068
ClinPred
0.69
D
GERP RS
4.8
Varity_R
0.14
gMVP
0.75

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.080
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: rs750582696; hg19: chr22-21350074; API