rs756876

Variant names:

• chr22-20992430-A-C
• rs756876
• NM_006767.4:c.1149+61A>C

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.1149+61A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.62 in 1,510,680 control chromosomes in the GnomAD database, including 292,435 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.62 (29730 hom., cov: 33)
  • Exomes 𝑓: 0.62 (262705 hom.)
• Consequence: LZTR1 NM_006767.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.297
• Publications: 12 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=-0.94).
• BP6: Variant 22-20992430-A-C is Benign according to our data. Variant chr22-20992430-A-C is described in ClinVar as [Benign]. Clinvar id is 561414.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.704 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LZTR1	NM_006767.4	c.1149+61A>C		intron_variant	Intron 10 of 20	ENST00000646124.2	NP_006758.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LZTR1	ENST00000646124.2	c.1149+61A>C		intron_variant	Intron 10 of 20		NM_006767.4	ENSP00000496779.1

Frequencies

GnomAD3 genomes AF: 0.622 AC: 94501 AN: 151882 Hom.: 29698 Cov.: 33

Gnomad AFR AF: 0.631

Gnomad AMI AF: 0.603

Gnomad AMR AF: 0.714

Gnomad ASJ AF: 0.580

Gnomad EAS AF: 0.596

Gnomad SAS AF: 0.454

Gnomad FIN AF: 0.558

Gnomad MID AF: 0.528

Gnomad NFE AF: 0.623

Gnomad OTH AF: 0.632

GnomAD4 exome AF: 0.620 AC: 841750 AN: 1358680 Hom.: 262705 Cov.: 21 AF XY: 0.615 AC XY: 413063 AN XY: 672020

African (AFR) AF: 0.620 AC: 19275 AN: 31068

American (AMR) AF: 0.787 AC: 28070 AN: 35670

Ashkenazi Jewish (ASJ) AF: 0.589 AC: 13694 AN: 23250

East Asian (EAS) AF: 0.616 AC: 22571 AN: 36620

South Asian (SAS) AF: 0.460 AC: 35744 AN: 77684

European-Finnish (FIN) AF: 0.576 AC: 26507 AN: 46008

Middle Eastern (MID) AF: 0.581 AC: 3200 AN: 5510

European-Non Finnish (NFE) AF: 0.629 AC: 658184 AN: 1046324

Other (OTH) AF: 0.610 AC: 34505 AN: 56546

GnomAD4 genome AF: 0.622 AC: 94583 AN: 152000 Hom.: 29730 Cov.: 33 AF XY: 0.618 AC XY: 45900 AN XY: 74280

African (AFR) AF: 0.630 AC: 26141 AN: 41470

American (AMR) AF: 0.715 AC: 10940 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.580 AC: 2012 AN: 3470

East Asian (EAS) AF: 0.596 AC: 3073 AN: 5158

South Asian (SAS) AF: 0.455 AC: 2193 AN: 4818

European-Finnish (FIN) AF: 0.558 AC: 5881 AN: 10544

Middle Eastern (MID) AF: 0.531 AC: 156 AN: 294

European-Non Finnish (NFE) AF: 0.623 AC: 42311 AN: 67926

Other (OTH) AF: 0.629 AC: 1327 AN: 2110

Alfa AF: 0.620 Hom.: 43192

Bravo AF: 0.641

Asia WGS AF: 0.533 AC: 1851 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jun 14, 2018

GeneDx

Significance: 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	7.2
DANN	Benign	0.56
PhyloP100		-0.30
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: rs756876; hg19: chr22-21346719; COSMIC: COSV53145677; COSMIC: COSV53145677;