22-20982374-G-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PVS1_StrongPM2

The NM_006767.4(LZTR1):​c.3G>T​(p.Met1?) variant causes a start lost change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Consequence

LZTR1
NM_006767.4 start_lost

Scores

3
3
10

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.33
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]

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

PVS1
Start lost variant, next in-frame start position is after 5 pathogenic variants. Next in-frame start position is after 270 CDS bases. Genomic position: 20985847. Lost 0.107 part of the original CDS.
PM2
Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
LZTR1NM_006767.4 linkc.3G>T p.Met1? start_lost Exon 1 of 21 ENST00000646124.2 NP_006758.2 Q8N653A0A384NL67

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
LZTR1ENST00000646124.2 linkc.3G>T p.Met1? start_lost Exon 1 of 21 NM_006767.4 ENSP00000496779.1 Q8N653

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
Cov.:
32
GnomAD4 genome
Cov.:
33

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not provided Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpMar 08, 2022Disruption of the initiator codon has been observed in individual(s) with autosomal recessive Noonan syndrome (PMID: 33897756). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is not present in population databases (gnomAD no frequency). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. 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. This sequence change affects the initiator methionine of the LZTR1 mRNA. The next in-frame methionine is located at codon 91. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
0.63
D
BayesDel_noAF
Benign
-0.31
CADD
Uncertain
24
DANN
Uncertain
0.98
DEOGEN2
Benign
0.025
T;T;.
Eigen
Benign
-0.021
Eigen_PC
Benign
0.13
FATHMM_MKL
Uncertain
0.89
D
LIST_S2
Uncertain
0.90
.;D;D
M_CAP
Pathogenic
0.41
D
MetaRNN
Pathogenic
0.95
D;D;D
MetaSVM
Benign
-1.0
T
PROVEAN
Benign
-0.080
N;.;.
REVEL
Benign
0.16
Sift
Benign
0.045
D;.;.
Sift4G
Benign
0.13
T;.;.
Polyphen
0.067
B;B;.
Vest4
0.65
MutPred
0.85
Loss of glycosylation at P4 (P = 0.0873);Loss of glycosylation at P4 (P = 0.0873);Loss of glycosylation at P4 (P = 0.0873);
MVP
0.17
ClinPred
0.96
D
GERP RS
5.2
RBP_binding_hub_radar
0.97
RBP_regulation_power_radar
2.8
Varity_R
0.48
gMVP
0.47

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr22-21336663; API