3-45828480-C-T

Position:

• chr3-45828480-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_020347.4(LZTFL1):​c.736G>A​(p.Asp246Asn) variant causes a missense change. The variant allele was found at a frequency of 0.0766 in 1,614,000 control chromosomes in the GnomAD database, including 5,091 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.069 (431 hom., cov: 32)
  • Exomes 𝑓: 0.077 (4660 hom.)
• Consequence: LZTFL1 NM_020347.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 4.52

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0027333498).
• BP6: Variant 3-45828480-C-T is Benign according to our data. Variant chr3-45828480-C-T is described in ClinVar as [Benign]. Clinvar id is 1164870.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.081 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LZTFL1	NM_020347.4	c.736G>A	p.Asp246Asn	missense_variant	8/10	ENST00000296135.11	NP_065080.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LZTFL1	ENST00000296135.11	c.736G>A	p.Asp246Asn	missense_variant	8/10	1	NM_020347.4	ENSP00000296135.6

Frequencies

GnomAD3 genomes AF: 0.0689 AC: 10481 AN: 152138 Hom.: 431 Cov.: 32

Gnomad AFR AF: 0.0395

Gnomad AMI AF: 0.0526

Gnomad AMR AF: 0.0532

Gnomad ASJ AF: 0.0666

Gnomad EAS AF: 0.0344

Gnomad SAS AF: 0.0739

Gnomad FIN AF: 0.134

Gnomad MID AF: 0.0665

Gnomad NFE AF: 0.0828

Gnomad OTH AF: 0.0684

GnomAD3 exomes AF: 0.0737 AC: 18532 AN: 251412 Hom.: 786 AF XY: 0.0758 AC XY: 10305 AN XY: 135880

Gnomad AFR exome AF: 0.0407

Gnomad AMR exome AF: 0.0403

Gnomad ASJ exome AF: 0.0676

Gnomad EAS exome AF: 0.0426

Gnomad SAS exome AF: 0.0746

Gnomad FIN exome AF: 0.135

Gnomad NFE exome AF: 0.0823

Gnomad OTH exome AF: 0.0730

GnomAD4 exome AF: 0.0774 AC: 113181 AN: 1461744 Hom.: 4660 Cov.: 32 AF XY: 0.0777 AC XY: 56509 AN XY: 727192

Gnomad4 AFR exome AF: 0.0406

Gnomad4 AMR exome AF: 0.0416

Gnomad4 ASJ exome AF: 0.0622

Gnomad4 EAS exome AF: 0.0518

Gnomad4 SAS exome AF: 0.0739

Gnomad4 FIN exome AF: 0.134

Gnomad4 NFE exome AF: 0.0791

Gnomad4 OTH exome AF: 0.0722

GnomAD4 genome AF: 0.0688 AC: 10481 AN: 152256 Hom.: 431 Cov.: 32 AF XY: 0.0706 AC XY: 5252 AN XY: 74442

Gnomad4 AFR AF: 0.0395

Gnomad4 AMR AF: 0.0530

Gnomad4 ASJ AF: 0.0666

Gnomad4 EAS AF: 0.0345

Gnomad4 SAS AF: 0.0740

Gnomad4 FIN AF: 0.134

Gnomad4 NFE AF: 0.0828

Gnomad4 OTH AF: 0.0676

Alfa AF: 0.0745 Hom.: 960

Bravo AF: 0.0611

TwinsUK AF: 0.0912 AC: 338

ALSPAC AF: 0.0812 AC: 313

ESP6500AA AF: 0.0431 AC: 190

ESP6500EA AF: 0.0798 AC: 686

ExAC AF: 0.0737 AC: 8948

Asia WGS AF: 0.0660 AC: 230 AN: 3478

EpiCase AF: 0.0790

EpiControl AF: 0.0772

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 30, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.088
BayesDel_addAF	Benign	-0.61	T
BayesDel_noAF	Benign	-0.58
CADD	Uncertain	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.0062	T;.;.
Eigen	Benign	0.15
Eigen_PC	Benign	0.14
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.90	D;D;D
MetaRNN	Benign	0.0027	T;T;T
MetaSVM	Benign	-0.86	T
MutationAssessor	Uncertain	2.2	M;.;.
MutationTaster	Benign	0.00015	P;P;P
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-1.3	N;N;N
REVEL	Benign	0.13
Sift	Uncertain	0.013	D;D;D
Sift4G	Uncertain	0.027	D;D;D
Polyphen		0.94	P;.;.
Vest4		0.14
MPC		0.94
ClinPred		0.013	T
GERP RS		4.9
Varity_R		0.11
gMVP		0.29

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

Publications

LitVar

Other links and lift over

dbSNP: rs1129183; hg19: chr3-45869972; COSMIC: COSV56111224; COSMIC: COSV56111224;