22-20990616-A-G

Variant names:

• chr22-20990616-A-G
• rs178290
• NM_006767.4:c.791+91A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_006767.4(LZTR1):​c.791+91A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.756 in 1,359,724 control chromosomes in the GnomAD database, including 389,877 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.74 (41671 hom., cov: 33)
  • Exomes 𝑓: 0.76 (348206 hom.)
• Consequence: LZTR1 NM_006767.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.904
• Publications: 8 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 22-20990616-A-G is Benign according to our data. Variant chr22-20990616-A-G is described in ClinVar as Benign. ClinVar VariationId is 561412.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.804 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006767.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LZTR1	NM_006767.4	MANE Select	c.791+91A>G		intron	N/A	NP_006758.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LZTR1	ENST00000646124.2	MANE Select	c.791+91A>G		intron	N/A	ENSP00000496779.1
	LZTR1	ENST00000497716.5	TSL:5	n.*128A>G		non_coding_transcript_exon	Exon 2 of 5	ENSP00000494153.1
	LZTR1	ENST00000497716.5	TSL:5	n.*128A>G		3_prime_UTR	Exon 2 of 5	ENSP00000494153.1

Frequencies

GnomAD3 genomes AF: 0.738 AC: 112158 AN: 152012 Hom.: 41636 Cov.: 33

Gnomad AFR AF: 0.702

Gnomad AMI AF: 0.749

Gnomad AMR AF: 0.815

Gnomad ASJ AF: 0.738

Gnomad EAS AF: 0.758

Gnomad SAS AF: 0.607

Gnomad FIN AF: 0.682

Gnomad MID AF: 0.680

Gnomad NFE AF: 0.758

Gnomad OTH AF: 0.756

GnomAD4 exome AF: 0.758 AC: 915037 AN: 1207594 Hom.: 348206 Cov.: 16 AF XY: 0.753 AC XY: 452278 AN XY: 600566

African (AFR) AF: 0.691 AC: 19127 AN: 27676

American (AMR) AF: 0.870 AC: 30626 AN: 35192

Ashkenazi Jewish (ASJ) AF: 0.745 AC: 14887 AN: 19974

East Asian (EAS) AF: 0.781 AC: 29700 AN: 38022

South Asian (SAS) AF: 0.610 AC: 42390 AN: 69514

European-Finnish (FIN) AF: 0.696 AC: 33343 AN: 47922

Middle Eastern (MID) AF: 0.723 AC: 3636 AN: 5030

European-Non Finnish (NFE) AF: 0.770 AC: 703326 AN: 913242

Other (OTH) AF: 0.745 AC: 38002 AN: 51022

GnomAD4 genome AF: 0.738 AC: 112244 AN: 152130 Hom.: 41671 Cov.: 33 AF XY: 0.735 AC XY: 54666 AN XY: 74360

African (AFR) AF: 0.702 AC: 29114 AN: 41498

American (AMR) AF: 0.816 AC: 12475 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.738 AC: 2563 AN: 3472

East Asian (EAS) AF: 0.758 AC: 3914 AN: 5164

South Asian (SAS) AF: 0.608 AC: 2935 AN: 4826

European-Finnish (FIN) AF: 0.682 AC: 7218 AN: 10578

Middle Eastern (MID) AF: 0.684 AC: 201 AN: 294

European-Non Finnish (NFE) AF: 0.758 AC: 51548 AN: 67978

Other (OTH) AF: 0.754 AC: 1594 AN: 2114

Alfa AF: 0.745 Hom.: 8602

Bravo AF: 0.754

Asia WGS AF: 0.680 AC: 2363 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	1.3
DANN	Benign	0.32
PhyloP100		-0.90
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism (auto)

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: rs178290; hg19: chr22-21344905; COSMIC: COSV104394195; COSMIC: COSV104394195;