22-20982374-G-T

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PS1_Moderate PM2

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
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.33

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]

ACMG classification

Verdict is Pathogenic. Variant got 12 ACMG points.

• PVS1: Start lost variant, no new inframe start found.
• PS1: Another start lost variant in NM_006767.4 (LZTR1) was described as [Conflicting_classifications_of_pathogenicity] in ClinVar as 1403744
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LZTR1	NM_006767.4	c.3G>T	p.Met1?	start_lost	1/21	ENST00000646124.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LZTR1	ENST00000646124.2	c.3G>T	p.Met1?	start_lost	1/21		NM_006767.4	P1

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

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Mar 08, 2022

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. Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. Disruption 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). 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
M_CAP	Pathogenic	0.41	D
MetaRNN	Pathogenic	0.95	D;D;D
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	D;D
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;