3-45827459-C-A

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PVS1PM2PP5

The NM_020347.4(LZTFL1):c.778G>T(p.Glu260*) variant causes a stop gained, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000208 in 1,441,776 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (no stars). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

LZTFL1
NM_020347.4 stop_gained, splice_region

Scores

Splicing: ADA: 0.9999

Clinical Significance

Pathogenic no assertion criteria provided P:1O:1

Conservation

PhyloP100: 7.50

Publications

2 publications found

Variant links:

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

LZTFL1 links:

ENSG00000288720 (HGNC:):

ENSG00000288720 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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 3-45827459-C-A is Pathogenic according to our data. Variant chr3-45827459-C-A is described in CliVar as Pathogenic. Clinvar id is 126381.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr3-45827459-C-A is described in CliVar as Pathogenic. Clinvar id is 126381.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr3-45827459-C-A is described in CliVar as Pathogenic. Clinvar id is 126381.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr3-45827459-C-A is described in CliVar as Pathogenic. Clinvar id is 126381.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr3-45827459-C-A is described in CliVar as Pathogenic. Clinvar id is 126381.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr3-45827459-C-A is described in CliVar as Pathogenic. Clinvar id is 126381.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr3-45827459-C-A is described in CliVar as Pathogenic. Clinvar id is 126381.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr3-45827459-C-A is described in CliVar as Pathogenic. Clinvar id is 126381.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr3-45827459-C-A is described in CliVar as Pathogenic. Clinvar id is 126381.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr3-45827459-C-A is described in CliVar as Pathogenic. Clinvar id is 126381.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr3-45827459-C-A is described in CliVar as Pathogenic. Clinvar id is 126381.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr3-45827459-C-A is described in CliVar as Pathogenic. Clinvar id is 126381.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr3-45827459-C-A is described in CliVar as Pathogenic. Clinvar id is 126381.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr3-45827459-C-A is described in CliVar as Pathogenic. Clinvar id is 126381.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr3-45827459-C-A is described in CliVar as Pathogenic. Clinvar id is 126381.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr3-45827459-C-A is described in CliVar as Pathogenic. Clinvar id is 126381.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr3-45827459-C-A is described in CliVar as Pathogenic. Clinvar id is 126381.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr3-45827459-C-A is described in CliVar as Pathogenic. Clinvar id is 126381.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr3-45827459-C-A is described in CliVar as Pathogenic. Clinvar id is 126381.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr3-45827459-C-A is described in CliVar as Pathogenic. Clinvar id is 126381.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LZTFL1	NM_020347.4 link	c.778G>T	p.Glu260*	stop_gained, splice_region_variant	Exon 9 of 10	ENST00000296135.11	NP_065080.1	Q9NQ48-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LZTFL1	ENST00000296135.11 link	c.778G>T	p.Glu260*	stop_gained, splice_region_variant	Exon 9 of 10	1	NM_020347.4	ENSP00000296135.6		Q9NQ48-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000798

AC:

AN:

250564

AF XY:

0.00000738

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000882

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000208

AC:

AN:

1441776

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

718590

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

33038

American (AMR)

AF:

0.00

AC:

AN:

44636

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26000

East Asian (EAS)

AF:

0.00

AC:

AN:

39588

South Asian (SAS)

AF:

0.0000117

AC:

AN:

85714

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53152

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5730

European-Non Finnish (NFE)

AF:

9.14e-7

AC:

AN:

1094288

Other (OTH)

AF:

0.0000168

AC:

AN:

59630

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.001943), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.358

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1Other:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

Bardet-Biedl syndrome 17

Pathogenic:1

May 01, 2014

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Bardet-Biedl syndrome 1

Other:1

GeneReviews

Significance:not provided

Review Status:no classification provided

Collection Method:literature only

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.55

BayesDel_noAF

Pathogenic

0.65

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

Eigen

Pathogenic

1.1

Eigen_PC

Pathogenic

0.98

FATHMM_MKL

Pathogenic

0.99

PhyloP100

7.5

Vest4

0.46

ClinPred

1.0

GERP RS

5.0

Mutation Taster

=0/200

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

SpliceAI score (max)

0.030

Details are displayed if max score is > 0.2

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over