chr3-45837991-G-A

Variant names:

• chr3-45837991-G-A
• rs1335038702
• NM_020347.4:c.64C>T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_020347.4(LZTFL1):​c.64C>T​(p.Arg22Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,274 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R22H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: LZTFL1 NM_020347.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.50
• Publications: 0 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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.64C>T	p.Arg22Cys	missense	Exon 2 of 10	NP_065080.1
	LZTFL1	NM_001405920.1		c.88C>T	p.Arg30Cys	missense	Exon 3 of 11	NP_001392849.1
	LZTFL1	NM_001276378.2		c.13C>T	p.Arg5Cys	missense	Exon 4 of 12	NP_001263307.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LZTFL1	ENST00000296135.11	TSL:1 MANE Select	c.64C>T	p.Arg22Cys	missense	Exon 2 of 10	ENSP00000296135.6
	LZTFL1	ENST00000684620.1		c.13C>T	p.Arg5Cys	missense	Exon 3 of 11	ENSP00000506925.1
	LZTFL1	ENST00000445698.1	TSL:5	c.13C>T	p.Arg5Cys	missense	Exon 2 of 3	ENSP00000412240.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000120 AC: 3 AN: 250732 AF XY: 0.0000148

Gnomad AFR exome AF: 0.0000616

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: 0.00000881

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461274 Hom.: 0 Cov.: 30 AF XY: 0.00000413 AC XY: 3 AN XY: 726966

African (AFR) AF: 0.0000299 AC: 1 AN: 33454

American (AMR) AF: 0.00 AC: 0 AN: 44590

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26122

East Asian (EAS) AF: 0.00 AC: 0 AN: 39666

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86098

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53388

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111826

Other (OTH) AF: 0.00 AC: 0 AN: 60364

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000312 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Bardet-Biedl syndrome 17 Uncertain:1

Dec 18, 2017

Genomic Research Center, Shahid Beheshti University of Medical Sciences

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.28
BayesDel_addAF	Uncertain	0.082	D
BayesDel_noAF	Uncertain	0.060
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.076	T
Eigen	Benign	-0.076
Eigen_PC	Benign	0.049
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.93	D
M_CAP	Benign	0.029	D
MetaRNN	Uncertain	0.51	D
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.6	L
PhyloP100		7.5
PrimateAI	Pathogenic	0.82	D
PROVEAN	Pathogenic	-5.1	D
REVEL	Uncertain	0.29
Sift	Pathogenic	0.0	D
Sift4G	Benign	0.076	T
Polyphen		0.22	B
Vest4		0.61
MutPred		0.37		Loss of MoRF binding (P = 0.015)
MVP		0.37
MPC		0.81
ClinPred		0.93	D
GERP RS		3.8
Varity_R		0.70
gMVP		0.88
Mutation Taster		=43/57	disease causing

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: rs1335038702; hg19: chr3-45879483; COSMIC: COSV56110793; COSMIC: COSV56110793;