22-20985848-ATG-GTC

Variant names:

• chr22-20985848-ATG-GTC
• NM_006767.4:c.271_273delATGinsGTC
• LZTR1 p.Met91Val

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM5 PP3

The NM_006767.4(LZTR1):​c.271_273delATGinsGTC​(p.Met91Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. It is difficult to determine the true allele frequency of this variant because it is of type MNV, and the frequency of such variant types in population databases may be underestimated and unreliable. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M91I) has been classified as Likely pathogenic. The gene LZTR1 is included in the ClinGen Criteria Specification Registry.

• Frequency: Genomes: not found (cov: 33)
• Consequence: LZTR1 NM_006767.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 9.44
• 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, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
• Noonan syndrome 10

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

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

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

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

  Inheritance: AD Classification: MODERATE Submitted by: G2P
• Costello syndrome

  Inheritance: AD, AR Classification: NO_KNOWN Submitted by: ClinGen
• Noonan syndrome with multiple lentigines

  Inheritance: AD, AR Classification: NO_KNOWN Submitted by: ClinGen
• cardiofaciocutaneous syndrome

  Inheritance: AR, AD Classification: NO_KNOWN Submitted by: ClinGen
• Noonan syndrome-like disorder with loose anagen hair

  Inheritance: AR, AD Classification: NO_KNOWN Submitted by: ClinGen

ENSG00000285314 (HGNC:):

ACMG classification

Specifications for LZTR1 are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM5: Other missense variant is known to change same aminoacid residue: Variant chr22-20985850-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 2636997.
• PP3: No computational evidence supports a deleterious effect, but strongly conserved according to phyloP

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.271_273delATGinsGTC	p.Met91Val	missense	N/A	NP_006758.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LZTR1	ENST00000646124.2	MANE Select	c.271_273delATGinsGTC	p.Met91Val	missense	N/A	ENSP00000496779.1	Q8N653
	LZTR1	ENST00000888029.1		c.271_273delATGinsGTC	p.Met91Val	missense	N/A	ENSP00000558088.1
	LZTR1	ENST00000888032.1		c.271_273delATGinsGTC	p.Met91Val	missense	N/A	ENSP00000558091.1

Frequencies

GnomAD3 genomes Cov.: 33

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		9.4

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

hg19: chr22-21340137;