Genetic Variant NM_006767.4:c.2062C>A (chr22-20995865-C-A) – ACMG Classification: Likely_pathogenic (6 pts)

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1PM2PP3_Moderate

The NM_006767.4(LZTR1):c.2062C>A(p.Arg688Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00000205 in 1,460,692 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

LZTR1
NM_006767.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.03

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]

LZTR1 links:

ENSG00000285314 (HGNC:):

ENSG00000285314 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

PM1

In a domain BTB 2 (size 69) in uniprot entity LZTR1_HUMAN there are 5 pathogenic changes around while only 0 benign (100%) in NM_006767.4

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.88

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LZTR1	NM_006767.4 link	c.2062C>A	p.Arg688Ser	missense_variant	Exon 17 of 21	ENST00000646124.2	NP_006758.2	Q8N653A0A384NL67

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LZTR1	ENST00000646124.2 link	c.2062C>A	p.Arg688Ser	missense_variant	Exon 17 of 21		NM_006767.4	ENSP00000496779.1		Q8N653

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000205

AC:

AN:

1460692

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

726674

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:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000270

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Hereditary cancer-predisposing syndrome;CN230736:Cardiovascular phenotype

Uncertain:1

Jul 06, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.R688S variant (also known as c.2062C>A), located in coding exon 17 of the LZTR1 gene, results from a C to A substitution at nucleotide position 2062. The arginine at codon 688 is replaced by serine, an amino acid with dissimilar properties. This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, the clinical significance of this variant remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.26

BayesDel_noAF

Pathogenic

0.14

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.57

D;D

Eigen

Pathogenic

0.69

Eigen_PC

Pathogenic

0.68

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.97

.;D

M_CAP

Pathogenic

0.31

MetaRNN

Pathogenic

0.88

D;D

MetaSVM

Uncertain

-0.15

MutationAssessor

Uncertain

2.2

M;M

PrimateAI

Pathogenic

0.84

PROVEAN

Pathogenic

-4.6

D;.

REVEL

Pathogenic

0.67

Sift

Pathogenic

0.0

D;.

Sift4G

Uncertain

0.0040

D;.

Polyphen

0.99

D;D

Vest4

0.84

MutPred

0.64

Loss of methylation at R688 (P = 0.0619);Loss of methylation at R688 (P = 0.0619);

MVP

0.46

MPC

0.37

ClinPred

1.0

GERP RS

4.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.85

gMVP

0.94

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over