rs199775294

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_001127671.2(LIFR):c.2074C>T(p.Arg692*) variant causes a stop gained change. The variant allele was found at a frequency of 0.0000318 in 1,475,820 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000033 ( 0 hom. )

Consequence

LIFR
NM_001127671.2 stop_gained

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4

Conservation

PhyloP100: 3.61

Publications

7 publications found

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 Gene-Disease associations (from GenCC):

Stüve-Wiedemann syndrome
Inheritance: AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
Stüve-Wiedemann syndrome 1
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)

LIFR links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 18 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 5-38490283-G-A is Pathogenic according to our data. Variant chr5-38490283-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 189235.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LIFR	NM_001127671.2 link	c.2074C>T	p.Arg692*	stop_gained	Exon 15 of 20	ENST00000453190.7	NP_001121143.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
LIFR	ENST00000453190.7 link	c.2074C>T	p.Arg692*	stop_gained	Exon 15 of 20	2	NM_001127671.2	ENSP00000398368.2
LIFR	ENST00000263409.8 link	c.2074C>T	p.Arg692*	stop_gained	Exon 15 of 20	1		ENSP00000263409.4
LIFR	ENST00000506003.5 link	n.*252C>T		non_coding_transcript_exon_variant	Exon 5 of 7	3		ENSP00000426919.1
LIFR	ENST00000506003.5 link	n.*252C>T		3_prime_UTR_variant	Exon 5 of 7	3		ENSP00000426919.1

Frequencies

GnomAD3 genomes

AF:

0.0000198

AC:

AN:

151810

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.000576

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000404

AC:

AN:

247352

AF XY:

0.0000224

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.000800

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000889

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000332

AC:

AN:

1324010

Hom.:

Cov.:

AF XY:

0.0000301

AC XY:

AN XY:

665544

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

30760

American (AMR)

AF:

0.00

AC:

AN:

43794

Ashkenazi Jewish (ASJ)

AF:

0.00103

AC:

AN:

25170

East Asian (EAS)

AF:

0.00

AC:

AN:

38716

South Asian (SAS)

AF:

0.0000123

AC:

AN:

81482

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52986

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5396

European-Non Finnish (NFE)

AF:

0.0000141

AC:

AN:

990094

Other (OTH)

AF:

0.0000539

AC:

AN:

55612

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.443

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

AF:

0.0000198

AC:

AN:

151810

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74128

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41316

American (AMR)

AF:

0.00

AC:

AN:

15242

Ashkenazi Jewish (ASJ)

AF:

0.000576

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5192

South Asian (SAS)

AF:

0.00

AC:

AN:

4812

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10492

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

67968

Other (OTH)

AF:

0.00

AC:

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.508

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0000476

Hom.:

Bravo

AF:

0.0000227

ExAC

AF:

0.0000247

AC:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Stuve-Wiedemann syndrome

Pathogenic:2

Mar 19, 2014

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The Arg692X variant in LIFR gene has not been reported in the literature but has been identified in 1/1319 European chromosomes by the ClinSeq project. This nonsense variant leads to a premature termination codon at position 692, which is predicted to lead to a truncated or absent protein. Heterozygous loss of function of the LIFR gene is strongly associated with Stuve-Wiedemann syndrome (SWS). In summary, this variant is likely pathogenic, though additional studies are required to fully establish its clinical significance. -

Sep 01, 2014

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Stüve-Wiedemann syndrome 1

Pathogenic:1

Jun 10, 2024

Fulgent Genetics, Fulgent Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Pathogenic:1

Jan 18, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change creates a premature translational stop signal (p.Arg692*) in the LIFR gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in LIFR are known to be pathogenic (PMID: 14740318). This variant is present in population databases (rs199775294, gnomAD 0.08%). This premature translational stop signal has been observed in individuals with Stuve-Wiedemann syndrome (PMID: 24988918). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 189235). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.55

BayesDel_noAF

Pathogenic

0.63

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

Eigen

Pathogenic

0.96

Eigen_PC

Pathogenic

0.85

FATHMM_MKL

Uncertain

0.96

PhyloP100

3.6

Vest4

0.93

GERP RS

6.0

Mutation Taster

=0/200

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.41

Details are displayed if max score is > 0.2

DS_AL_spliceai

0.41

Position offset: 8

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

Publications

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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