rs2303743

Variant names:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001127671.2(LIFR):c.1899A>G(p.Ile633Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00371 in 1,613,954 control chromosomes in the GnomAD database, including 93 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0072 ( 18 hom., cov: 32)

Exomes 𝑓: 0.0034 ( 75 hom. )

Consequence

LIFR
NM_001127671.2 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: -0.102

Variant links:

Genes affected

LIFR (HGNC:6597): (LIF receptor subunit alpha) This gene encodes a protein that belongs to the type I cytokine receptor family. This protein combines with a high-affinity converter subunit, gp130, to form a receptor complex that mediates the action of the leukemia inhibitory factor, a polyfunctional cytokine that is involved in cellular differentiation, proliferation and survival in the adult and the embryo. Mutations in this gene cause Schwartz-Jampel syndrome type 2, a disease belonging to the group of the bent-bone dysplasias. A translocation that involves the promoter of this gene, t(5;8)(p13;q12) with the pleiomorphic adenoma gene 1, is associated with salivary gland pleiomorphic adenoma, a common type of benign epithelial tumor of the salivary gland. Multiple splice variants encoding two different isoforms have been found for this gene. [provided by RefSeq, Jun 2018]

LIFR links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0020363927).

BP6

Variant 5-38493772-T-C is Benign according to our data. Variant chr5-38493772-T-C is described in ClinVar as [Benign]. Clinvar id is 194373.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-38493772-T-C is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00717 (1092/152328) while in subpopulation AMR AF= 0.0336 (515/15306). AF 95% confidence interval is 0.0312. There are 18 homozygotes in gnomad4. There are 610 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 18 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LIFR	NM_001127671.2 link	c.1899A>G	p.Ile633Met	missense_variant	Exon 14 of 20	ENST00000453190.7	NP_001121143.1	P42702-1A8K1Z4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LIFR	ENST00000453190.7 link	c.1899A>G	p.Ile633Met	missense_variant	Exon 14 of 20	2	NM_001127671.2	ENSP00000398368.2		P42702-1

Frequencies

GnomAD3 genomes

AF:

0.00718

AC:

1093

AN:

152210

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00425

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0337

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.0167

Gnomad SAS

AF:

0.00103

Gnomad FIN

AF:

0.0170

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00171

Gnomad OTH

AF:

0.00574

GnomAD3 exomes

AF:

0.00893

AC:

2245

AN:

251436

Hom.:

AF XY:

0.00754

AC XY:

1024

AN XY:

135886

show subpopulations

Gnomad AFR exome

AF:

0.00406

Gnomad AMR exome

AF:

0.0353

Gnomad ASJ exome

AF:

0.0000992

Gnomad EAS exome

AF:

0.0145

Gnomad SAS exome

AF:

0.000817

Gnomad FIN exome

AF:

0.0208

Gnomad NFE exome

AF:

0.00131

Gnomad OTH exome

AF:

0.0106

GnomAD4 exome

AF:

0.00335

AC:

4900

AN:

1461626

Hom.:

Cov.:

AF XY:

0.00318

AC XY:

2314

AN XY:

727136

show subpopulations

Gnomad4 AFR exome

AF:

0.00415

Gnomad4 AMR exome

AF:

0.0350

Gnomad4 ASJ exome

AF:

0.0000383

Gnomad4 EAS exome

AF:

0.0273

Gnomad4 SAS exome

AF:

0.000730

Gnomad4 FIN exome

AF:

0.0199

Gnomad4 NFE exome

AF:

0.000670

Gnomad4 OTH exome

AF:

0.00383

GnomAD4 genome

AF:

0.00717

AC:

1092

AN:

152328

Hom.:

Cov.:

AF XY:

0.00819

AC XY:

610

AN XY:

74496

show subpopulations

Gnomad4 AFR

AF:

0.00423

Gnomad4 AMR

AF:

0.0336

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.0168

Gnomad4 SAS

AF:

0.00104

Gnomad4 FIN

AF:

0.0170

Gnomad4 NFE

AF:

0.00171

Gnomad4 OTH

AF:

0.00568

Alfa

AF:

0.00277

Hom.:

Bravo

AF:

0.00730

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.00431

AC:

ESP6500EA

AF:

0.000930

AC:

ExAC

AF:

0.00713

AC:

865

Asia WGS

AF:

0.0110

AC:

AN:

3478

EpiCase

AF:

0.000327

EpiControl

AF:

0.000178

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

Jan 30, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 21, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 05, 2017

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Stuve-Wiedemann syndrome

Benign:2

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Sep 16, 2020

Natera, Inc.

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not specified

Benign:1

Jan 06, 2015

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Stüve-Wiedemann syndrome 1

Benign:1

Nov 08, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Connective tissue disorder

Benign:1

Oct 01, 2018

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.067

BayesDel_addAF

Benign

-0.60

BayesDel_noAF

Benign

-0.60

CADD

Benign

DANN

Benign

0.79

DEOGEN2

Benign

0.30

T;T

Eigen

Benign

-0.76

Eigen_PC

Benign

-0.63

FATHMM_MKL

Benign

0.73

LIST_S2

Benign

0.56

.;T

MetaRNN

Benign

0.0020

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

-0.20

N;N

PrimateAI

Benign

0.32

PROVEAN

Benign

-0.27

N;N

REVEL

Benign

0.052

Sift

Benign

0.095

T;T

Sift4G

Benign

0.33

T;T

Polyphen

0.0020

B;B

Vest4

0.097

MVP

0.30

MPC

0.087

ClinPred

0.0037

GERP RS

-0.20

Varity_R

0.061

gMVP

0.35

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over