22-20982366-C-T

Position:

chr22-20982366-C-T

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 0P and 18B. BP4_ModerateBP6_Very_StrongBS1BS2

The NM_006767.4(LZTR1):c.-6C>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00129 in 1,548,182 control chromosomes in the GnomAD database, including 34 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.00097 ( 2 hom., cov: 33)

Exomes 𝑓: 0.0013 ( 32 hom. )

Consequence

LZTR1
NM_006767.4 5_prime_UTR

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: -0.169

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -18 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.45).

BP6

Variant 22-20982366-C-T is Benign according to our data. Variant chr22-20982366-C-T is described in ClinVar as [Benign]. Clinvar id is 928479.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.000971 (148/152342) while in subpopulation EAS AF= 0.0216 (112/5176). AF 95% confidence interval is 0.0184. There are 2 homozygotes in gnomad4. There are 74 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 2 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LZTR1	NM_006767.4 linkuse as main transcript	c.-6C>T		5_prime_UTR_variant	1/21	ENST00000646124.2	NP_006758.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LZTR1	ENST00000646124.2 linkuse as main transcript	c.-6C>T		5_prime_UTR_variant	1/21		NM_006767.4	ENSP00000496779	P1

Frequencies

GnomAD3 genomes

AF:

0.000966

AC:

147

AN:

152224

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000523

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.0216

Gnomad SAS

AF:

0.00207

Gnomad FIN

AF:

0.000282

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000206

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00188

AC:

280

AN:

148602

Hom.:

AF XY:

0.00196

AC XY:

157

AN XY:

79954

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000933

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0191

Gnomad SAS exome

AF:

0.00109

Gnomad FIN exome

AF:

0.000271

Gnomad NFE exome

AF:

0.000289

Gnomad OTH exome

AF:

0.000474

GnomAD4 exome

AF:

0.00132

AC:

1846

AN:

1395840

Hom.:

Cov.:

AF XY:

0.00137

AC XY:

940

AN XY:

688182

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000728

Gnomad4 ASJ exome

AF:

0.0000799

Gnomad4 EAS exome

AF:

0.0412

Gnomad4 SAS exome

AF:

0.00137

Gnomad4 FIN exome

AF:

0.000609

Gnomad4 NFE exome

AF:

0.000138

Gnomad4 OTH exome

AF:

0.000831

GnomAD4 genome

AF:

0.000971

AC:

148

AN:

152342

Hom.:

Cov.:

AF XY:

0.000993

AC XY:

AN XY:

74488

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000522

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.0216

Gnomad4 SAS

AF:

0.00228

Gnomad4 FIN

AF:

0.000282

Gnomad4 NFE

AF:

0.000206

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000408

Hom.:

Bravo

AF:

0.000990

Asia WGS

AF:

0.0110

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Nov 18, 2019

Variant summary: LZTR1 c.-6C>T is located in the untranslated mRNA region upstream of the initiation codon. The variant allele was found at a frequency of 0.0019 in 148602 control chromosomes in the gnomAD database, including 3 homozygotes. The observed variant frequency is approximately 377 fold of the estimated maximal expected allele frequency for a pathogenic variant in LZTR1 causing Noonan Syndrome and Related Conditions phenotype (5e-06), strongly suggesting that the variant is benign. To our knowledge, no occurrence of c.-6C>T in individuals affected with Noonan Syndrome and Related Conditions and no experimental evidence demonstrating its impact on protein function have been reported. Co-occurrence with another pathogenic variant has been reported (PTPN11 c.922A>G, p.Asn308Asp) at our laboratory, providing supporting evidence for a benign role. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as benign. -

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jul 30, 2018

- -

LZTR1-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

May 30, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Noonan syndrome and Noonan-related syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Feb 04, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.45

CADD

Benign

DANN

Benign

0.94

RBP_binding_hub_radar

0.97

RBP_regulation_power_radar

2.1

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over