22-20990595-C-T

Variant names:

• chr22-20990595-C-T
• rs2073989
• NM_006767.4:c.791+70C>T

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+70C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.325 in 1,476,362 control chromosomes in the GnomAD database, including 84,127 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.27 (6511 hom., cov: 33)
  • Exomes 𝑓: 0.33 (77616 hom.)
• Consequence: LZTR1 NM_006767.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -3.79
• Publications: 10 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=-0.87).
• BP6: Variant 22-20990595-C-T is Benign according to our data. Variant chr22-20990595-C-T is described in ClinVar as Benign. ClinVar VariationId is 561411.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.37 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LZTR1	NM_006767.4	MANE Select	c.791+70C>T		intron	N/A	NP_006758.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LZTR1	ENST00000646124.2	MANE Select	c.791+70C>T		intron	N/A	ENSP00000496779.1
	LZTR1	ENST00000888029.1		c.791+70C>T		intron	N/A	ENSP00000558088.1
	LZTR1	ENST00000888032.1		c.791+70C>T		intron	N/A	ENSP00000558091.1

Frequencies

GnomAD3 genomes AF: 0.268 AC: 40792 AN: 152030 Hom.: 6500 Cov.: 33

Gnomad AFR AF: 0.131

Gnomad AMI AF: 0.418

Gnomad AMR AF: 0.377

Gnomad ASJ AF: 0.383

Gnomad EAS AF: 0.0645

Gnomad SAS AF: 0.154

Gnomad FIN AF: 0.211

Gnomad MID AF: 0.326

Gnomad NFE AF: 0.350

Gnomad OTH AF: 0.330

GnomAD4 exome AF: 0.332 AC: 439618 AN: 1324214 Hom.: 77616 Cov.: 20 AF XY: 0.328 AC XY: 214643 AN XY: 654534

African (AFR) AF: 0.122 AC: 3694 AN: 30338

American (AMR) AF: 0.401 AC: 14874 AN: 37108

Ashkenazi Jewish (ASJ) AF: 0.391 AC: 8281 AN: 21182

East Asian (EAS) AF: 0.0834 AC: 3227 AN: 38696

South Asian (SAS) AF: 0.155 AC: 11378 AN: 73258

European-Finnish (FIN) AF: 0.235 AC: 11761 AN: 49964

Middle Eastern (MID) AF: 0.355 AC: 1889 AN: 5316

European-Non Finnish (NFE) AF: 0.362 AC: 366962 AN: 1013314

Other (OTH) AF: 0.319 AC: 17552 AN: 55038

GnomAD4 genome AF: 0.268 AC: 40807 AN: 152148 Hom.: 6511 Cov.: 33 AF XY: 0.261 AC XY: 19404 AN XY: 74380

African (AFR) AF: 0.131 AC: 5428 AN: 41506

American (AMR) AF: 0.378 AC: 5767 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.383 AC: 1330 AN: 3470

East Asian (EAS) AF: 0.0643 AC: 333 AN: 5178

South Asian (SAS) AF: 0.154 AC: 745 AN: 4828

European-Finnish (FIN) AF: 0.211 AC: 2232 AN: 10600

Middle Eastern (MID) AF: 0.337 AC: 99 AN: 294

European-Non Finnish (NFE) AF: 0.350 AC: 23801 AN: 67974

Other (OTH) AF: 0.327 AC: 691 AN: 2116

Alfa AF: 0.320 Hom.: 21138

Bravo AF: 0.282

Asia WGS AF: 0.113 AC: 393 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	-0.87
CADD	Benign	0.21
DANN	Benign	0.73
PhyloP100		-3.8
RBP_binding_hub_radar		0.97
RBP_regulation_power_radar		2.0
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: rs2073989; hg19: chr22-21344884; COSMIC: COSV104394210;