22-20982361-G-A

Variant names:

• chr22-20982361-G-A
• rs370616172
• NM_006767.4:c.-11G>A

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_006767.4(LZTR1):​c.-11G>A variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00134 in 1,546,152 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00096 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0014 (2 hom.)
• Consequence: LZTR1 NM_006767.4 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.409
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• LZTR1-related schwannomatosis

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• Noonan syndrome 10

  Inheritance: AD, AR Classification: DEFINITIVE, STRONG Submitted by: G2P, PanelApp Australia, Labcorp Genetics (formerly Invitae), Ambry Genetics, Genomics England PanelApp
• schwannomatosis

  Inheritance: AD Classification: DEFINITIVE Submitted by: G2P
• Noonan syndrome

  Inheritance: AR, AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, Orphanet
• Noonan syndrome 2

  Inheritance: AR Classification: STRONG, MODERATE Submitted by: Ambry Genetics, PanelApp Australia, Genomics England PanelApp
• breast cancer

  Inheritance: AD Classification: MODERATE Submitted by: G2P

ENSG00000285314 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -16 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.63).
• BP6: Variant 22-20982361-G-A is Benign according to our data. Variant chr22-20982361-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 389662.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAdExome4 at 2 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LZTR1	NM_006767.4	c.-11G>A		5_prime_UTR_premature_start_codon_gain_variant	Exon 1 of 21	ENST00000646124.2	NP_006758.2
LZTR1	NM_006767.4	c.-11G>A		5_prime_UTR_variant	Exon 1 of 21	ENST00000646124.2	NP_006758.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LZTR1	ENST00000646124.2	c.-11G>A		5_prime_UTR_premature_start_codon_gain_variant	Exon 1 of 21		NM_006767.4	ENSP00000496779.1
LZTR1	ENST00000646124.2	c.-11G>A		5_prime_UTR_variant	Exon 1 of 21		NM_006767.4	ENSP00000496779.1

Frequencies

GnomAD3 genomes AF: 0.000965 AC: 147 AN: 152262 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000265

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000659

Gnomad MID AF: 0.00318

Gnomad NFE AF: 0.00184

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000913 AC: 134 AN: 146760 AF XY: 0.000911

Gnomad AFR exome AF: 0.000139

Gnomad AMR exome AF: 0.000815

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000345

Gnomad NFE exome AF: 0.00183

Gnomad OTH exome AF: 0.00191

GnomAD4 exome AF: 0.00138 AC: 1925 AN: 1393772 Hom.: 2 Cov.: 32 AF XY: 0.00133 AC XY: 911 AN XY: 687012

African (AFR) AF: 0.000190 AC: 6 AN: 31554

American (AMR) AF: 0.000844 AC: 30 AN: 35548

Ashkenazi Jewish (ASJ) AF: 0.0000801 AC: 2 AN: 24982

East Asian (EAS) AF: 0.00 AC: 0 AN: 35746

South Asian (SAS) AF: 0.00 AC: 0 AN: 79290

European-Finnish (FIN) AF: 0.000508 AC: 24 AN: 47202

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5568

European-Non Finnish (NFE) AF: 0.00168 AC: 1813 AN: 1076146

Other (OTH) AF: 0.000866 AC: 50 AN: 57736

GnomAD4 genome AF: 0.000965 AC: 147 AN: 152380 Hom.: 0 Cov.: 33 AF XY: 0.000993 AC XY: 74 AN XY: 74516

African (AFR) AF: 0.000264 AC: 11 AN: 41594

American (AMR) AF: 0.000131 AC: 2 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.000659 AC: 7 AN: 10630

Middle Eastern (MID) AF: 0.00342 AC: 1 AN: 292

European-Non Finnish (NFE) AF: 0.00184 AC: 125 AN: 68036

Other (OTH) AF: 0.000473 AC: 1 AN: 2116

Alfa AF: 0.000647 Hom.: 0

Bravo AF: 0.00103

Asia WGS AF: 0.000289 AC: 1 AN: 3476

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Oct 07, 2016

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

May 28, 2020

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:1

Nov 04, 2019

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

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: LZTR1 c.-11G>A alters a non-conserved nucleotide located in the untranslated mRNA region upstream of the initiation codon. The variant allele was found at a frequency of 0.00091 in 146760 control chromosomes. The observed variant frequency is approximately 183 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.-11G>A in individuals affected with Noonan Syndrome and Related Conditions and no experimental evidence demonstrating its impact on protein function have been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as likely benign. Based on the evidence outlined above, the variant was classified as benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.63
CADD	Benign	18
DANN	Benign	0.92
PhyloP100		0.41
PromoterAI		0.13	Neutral
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.1
Mutation Taster		=300/0	polymorphism

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

Other links and lift over

dbSNP: rs370616172; hg19: chr22-21336650;