NM_020347.4:c.402_406delAAAGC

Variant names:

• chr3-45833099-GGCTTT-G
• rs431825171
• NM_020347.4:c.402_406delAAAGC

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PVS1 PM2 PP5

The NM_020347.4(LZTFL1):​c.402_406delAAAGC​(p.Pro136ThrfsTer5) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (no stars). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: LZTFL1 NM_020347.4 frameshift
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 7.31
• Publications: 2 publications found

Genes affected

LZTFL1 (HGNC:6741): (leucine zipper transcription factor like 1) This gene encodes a ubiquitously expressed protein that localizes to the cytoplasm. This protein interacts with Bardet-Biedl Syndrome (BBS) proteins and, through its interaction with BBS protein complexes, regulates protein trafficking to the ciliary membrane. Nonsense mutations in this gene cause a form of Bardet-Biedl Syndrome; a ciliopathy characterized in part by polydactyly, obesity, cognitive impairment, hypogonadism, and kidney failure. This gene may also function as a tumor suppressor; possibly by interacting with E-cadherin and the actin cytoskeleton and thereby regulating the transition of epithelial cells to mesenchymal cells. [provided by RefSeq, Aug 2020]

LZTFL1 Gene-Disease associations (from GenCC):

• ciliopathy

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• Bardet-Biedl syndrome 17

  Inheritance: AR Classification: STRONG, MODERATE Submitted by: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics
• Bardet-Biedl syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000288720 (HGNC:):

ACMG classification

Our verdict: Pathogenic. The variant received 11 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 3-45833099-GGCTTT-G is Pathogenic according to our data. Variant chr3-45833099-GGCTTT-G is described in ClinVar as Pathogenic. ClinVar VariationId is 39770.Status of the report is no_assertion_criteria_provided, 0 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_020347.4. 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
	LZTFL1	NM_020347.4	MANE Select	c.402_406delAAAGC	p.Pro136ThrfsTer5	frameshift	Exon 5 of 10	NP_065080.1
	LZTFL1	NM_001405920.1		c.426_430delAAAGC	p.Pro144ThrfsTer5	frameshift	Exon 6 of 11	NP_001392849.1
	LZTFL1	NM_001405921.1		c.390_394delAAAGC	p.Pro132ThrfsTer5	frameshift	Exon 6 of 11	NP_001392850.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LZTFL1	ENST00000296135.11	TSL:1 MANE Select	c.402_406delAAAGC	p.Pro136ThrfsTer5	frameshift	Exon 5 of 10	ENSP00000296135.6
	LZTFL1	ENST00000684620.1		c.351_355delAAAGC	p.Pro119ThrfsTer5	frameshift	Exon 6 of 11	ENSP00000506925.1
	LZTFL1	ENST00000539217.5	TSL:2	c.390_394delAAAGC	p.Pro132ThrfsTer5	frameshift	Exon 6 of 10	ENSP00000441784.1

Frequencies

GnomAD3 genomes Cov.: 32

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

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Bardet-Biedl syndrome 17 Pathogenic:1

May 01, 2012

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		7.3
Mutation Taster		=1/199	disease causing (ClinVar)

Splicing

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

Other links and lift over

dbSNP: rs431825171; hg19: chr3-45874591;