rs3729740

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001127671.2(LIFR):c.1732G>A(p.Asp578Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00888 in 1,613,952 control chromosomes in the GnomAD database, including 1,472 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.012 ( 181 hom., cov: 33)

Exomes 𝑓: 0.0086 ( 1291 hom. )

Consequence

LIFR
NM_001127671.2 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 0.467

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 was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0016947091).

BP6

Variant 5-38496535-C-T is Benign according to our data. Variant chr5-38496535-C-T is described in ClinVar as [Benign]. Clinvar id is 353625.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-38496535-C-T is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.237 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LIFR	NM_001127671.2 link	c.1732G>A	p.Asp578Asn	missense_variant	Exon 13 of 20	ENST00000453190.7	NP_001121143.1	P42702-1A8K1Z4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
LIFR	ENST00000453190.7 link	c.1732G>A	p.Asp578Asn	missense_variant	Exon 13 of 20	2	NM_001127671.2	ENSP00000398368.2	P42702-1
LIFR	ENST00000263409.8 link	c.1732G>A	p.Asp578Asn	missense_variant	Exon 13 of 20	1		ENSP00000263409.4	P42702-1
LIFR	ENST00000503088.1 link	n.1895G>A		non_coding_transcript_exon_variant	Exon 13 of 15	1
LIFR	ENST00000506003.5 link	n.109-1G>A		splice_acceptor_variant, intron_variant	Intron 2 of 6	3		ENSP00000426919.1	H0YAF2

Frequencies

GnomAD3 genomes

AF:

0.0115

AC:

1752

AN:

152188

Hom.:

180

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00164

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00766

Gnomad ASJ

AF:

0.000865

Gnomad EAS

AF:

0.248

Gnomad SAS

AF:

0.0120

Gnomad FIN

AF:

0.0120

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000999

Gnomad OTH

AF:

0.0105

GnomAD2 exomes

AF:

0.0220

AC:

5533

AN:

251410

AF XY:

0.0207

show subpopulations

Gnomad AFR exome

AF:

0.00123

Gnomad AMR exome

AF:

0.00778

Gnomad ASJ exome

AF:

0.000992

Gnomad EAS exome

AF:

0.253

Gnomad FIN exome

AF:

0.0105

Gnomad NFE exome

AF:

0.00110

Gnomad OTH exome

AF:

0.0112

GnomAD4 exome

AF:

0.00860

AC:

12566

AN:

1461646

Hom.:

1291

Cov.:

AF XY:

0.00850

AC XY:

6181

AN XY:

727136

show subpopulations

African (AFR)

AF:

0.000956

AC:

AN:

33476

American (AMR)

AF:

0.00812

AC:

363

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.000765

AC:

AN:

26134

East Asian (EAS)

AF:

0.245

AC:

9727

AN:

39686

South Asian (SAS)

AF:

0.00605

AC:

522

AN:

86252

European-Finnish (FIN)

AF:

0.00900

AC:

481

AN:

53420

Middle Eastern (MID)

AF:

0.00139

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000460

AC:

511

AN:

1111794

Other (OTH)

AF:

0.0149

AC:

902

AN:

60392

Heterozygous variant carriers

670

1341

2011

2682

3352

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Exome Het

Exome Hom

Variant carriers

170

340

510

680

850

<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

AF:

0.0116

AC:

1761

AN:

152306

Hom.:

181

Cov.:

AF XY:

0.0132

AC XY:

982

AN XY:

74474

show subpopulations

African (AFR)

AF:

0.00164

AC:

AN:

41556

American (AMR)

AF:

0.00830

AC:

127

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.000865

AC:

AN:

3470

East Asian (EAS)

AF:

0.248

AC:

1285

AN:

5186

South Asian (SAS)

AF:

0.0124

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.0120

AC:

127

AN:

10608

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000999

AC:

AN:

68040

Other (OTH)

AF:

0.0109

AC:

AN:

2116

Heterozygous variant carriers

143

214

286

357

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Genome Het

Genome Hom

Variant carriers

120

150

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00977

Hom.:

323

Bravo

AF:

0.0124

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.00136

AC:

ESP6500EA

AF:

0.00140

AC:

ExAC

AF:

0.0209

AC:

2541

Asia WGS

AF:

0.0970

AC:

337

AN:

3478

EpiCase

AF:

0.000600

EpiControl

AF:

0.000711

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Sep 29, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 29, 2025

Labcorp Genetics (formerly Invitae), Labcorp

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

Dec 02, 2019

Natera, Inc.

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.063

BayesDel_addAF

Benign

-0.77

BayesDel_noAF

Benign

-0.73

CADD

Benign

DANN

Benign

0.88

DEOGEN2

Benign

0.25

T;T

Eigen

Benign

-0.97

Eigen_PC

Benign

-0.86

FATHMM_MKL

Benign

0.053

LIST_S2

Benign

0.63

.;T

MetaRNN

Benign

0.0017

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-0.35

N;N

PrimateAI

Benign

0.28

PROVEAN

Benign

0.080

N;N

REVEL

Benign

0.035

Sift

Benign

0.61

T;T

Sift4G

Benign

0.92

T;T

Polyphen

0.0

B;B

Vest4

0.070

MPC

0.083

ClinPred

0.0048

GERP RS

1.9

Varity_R

0.038

gMVP

0.20

Mutation Taster

=99/1

polymorphism (auto)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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