22-20982376-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PM1 PM2 BP4_Moderate

The NM_006767.4(LZTR1):c.5C>T(p.Ala2Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A2G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: LZTR1 NM_006767.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.679

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 Uncertain_significance. Variant got 2 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 7 uncertain in NM_006767.4
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.20887917).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LZTR1	NM_006767.4	c.5C>T	p.Ala2Val	missense_variant	1/21	ENST00000646124.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LZTR1	ENST00000646124.2	c.5C>T	p.Ala2Val	missense_variant	1/21		NM_006767.4	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1399664 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 690452

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

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

Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden

Nov 03, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.38
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.47
Cadd	Pathogenic	26
Dann	Uncertain	1.0
DEOGEN2	Benign	0.034	T;T;.
Eigen	Benign	-0.26
Eigen_PC	Benign	-0.071
FATHMM_MKL	Uncertain	0.89	D
M_CAP	Uncertain	0.11	D
MetaRNN	Benign	0.21	T;T;T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	0.0	N;N;.
MutationTaster	Benign	0.78	D;D
PrimateAI	Uncertain	0.76	T
PROVEAN	Benign	-0.28	N;.;.
REVEL	Benign	0.046
Sift	Pathogenic	0.0	D;.;.
Sift4G	Uncertain	0.025	D;.;.
Polyphen		0.0	B;B;.
Vest4		0.17
MutPred		0.22		Loss of catalytic residue at M1 (P = 0.0459);Loss of catalytic residue at M1 (P = 0.0459);Loss of catalytic residue at M1 (P = 0.0459);
MVP		0.12
MPC		1.1
ClinPred		0.61	D
GERP RS		4.2
Varity_R		0.23
gMVP		0.45

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

LitVar

Other links and lift over

dbSNP: rs1924222609; hg19: chr22-21336665;