22-20982366-C-T

Variant names:

• chr22-20982366-C-T
• rs188063382
• NM_006767.4:c.-6C>T

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BS1 BS2

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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.169

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]

ENSG00000285314 (HGNC:):

ACMG classification

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 rank	MANE	Protein	UniProt
LZTR1	NM_006767.4	c.-6C>T		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	c.-6C>T		5_prime_UTR_variant	Exon 1 of 21		NM_006767.4	ENSP00000496779.1

Frequencies

GnomAD3 genomes AF: 0.000966 AC: 147 AN: 152224 Hom.: 2 Cov.: 33

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.: 3 AF XY: 0.00196 AC XY: 157 AN XY: 79954

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.: 32 Cov.: 32 AF XY: 0.00137 AC XY: 940 AN XY: 688182

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.: 2 Cov.: 33 AF XY: 0.000993 AC XY: 74 AN XY: 74488

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.: 0

Bravo AF: 0.000990

Asia WGS AF: 0.0110 AC: 38 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Nov 18, 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.-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

Jul 30, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

LZTR1-related disorder Benign:1

May 30, 2019

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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

Feb 04, 2021

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.45
CADD	Benign	15
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

Other links and lift over

dbSNP: rs188063382; hg19: chr22-21336655; COSMIC: COSV53152556; COSMIC: COSV53152556;