rs145163157

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_StrongBS1_Supporting

The NM_001127671.2(LIFR):c.364A>G(p.Thr122Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000219 in 1,593,666 control chromosomes in the GnomAD database, including 1 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 Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. T122T) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0012 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00011 ( 1 hom. )

Consequence

LIFR
NM_001127671.2 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4B:1

Conservation

PhyloP100: 0.151

Publications

2 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: Likely_benign. The variant received -5 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0052199364).

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00123 (187/152360) while in subpopulation AFR AF = 0.00418 (174/41590). AF 95% confidence interval is 0.00368. There are 0 homozygotes in GnomAd4. There are 85 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LIFR	NM_001127671.2 link	c.364A>G	p.Thr122Ala	missense_variant	Exon 4 of 20	ENST00000453190.7	NP_001121143.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
LIFR	ENST00000453190.7 link	c.364A>G	p.Thr122Ala	missense_variant	Exon 4 of 20	2	NM_001127671.2	ENSP00000398368.2
LIFR	ENST00000263409.8 link	c.364A>G	p.Thr122Ala	missense_variant	Exon 4 of 20	1		ENSP00000263409.4
LIFR	ENST00000503088.1 link	n.527A>G		non_coding_transcript_exon_variant	Exon 4 of 15	1
LIFR	ENST00000506990.5 link	c.364A>G	p.Thr122Ala	missense_variant	Exon 5 of 5	3		ENSP00000426685.1

Frequencies

GnomAD3 genomes

AF:

0.00122

AC:

186

AN:

152242

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00417

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000720

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.000955

GnomAD2 exomes

AF:

0.000256

AC:

AN:

246530

AF XY:

0.000165

show subpopulations

Gnomad AFR exome

AF:

0.00311

Gnomad AMR exome

AF:

0.000328

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000894

Gnomad OTH exome

AF:

0.000167

GnomAD4 exome

AF:

0.000112

AC:

162

AN:

1441306

Hom.:

Cov.:

AF XY:

0.0000919

AC XY:

AN XY:

717958

show subpopulations

African (AFR)

AF:

0.00336

AC:

111

AN:

32990

American (AMR)

AF:

0.000387

AC:

AN:

43984

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25864

East Asian (EAS)

AF:

0.00

AC:

AN:

39482

South Asian (SAS)

AF:

0.0000353

AC:

AN:

85012

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53280

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5704

European-Non Finnish (NFE)

AF:

9.13e-7

AC:

AN:

1095322

Other (OTH)

AF:

0.000503

AC:

AN:

59668

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.459

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

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:

0.00123

AC:

187

AN:

152360

Hom.:

Cov.:

AF XY:

0.00114

AC XY:

AN XY:

74504

show subpopulations

African (AFR)

AF:

0.00418

AC:

174

AN:

41590

American (AMR)

AF:

0.000719

AC:

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5188

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68036

Other (OTH)

AF:

0.000945

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome 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

Alfa

AF:

0.000476

Hom.:

Bravo

AF:

0.00153

ESP6500AA

AF:

0.00273

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000272

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:2Benign:1

Jan 23, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Oct 12, 2015

Eurofins Ntd Llc (ga)

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Dec 18, 2023

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Stuve-Wiedemann syndrome

Uncertain:2

Oct 31, 2018

Fulgent Genetics, Fulgent Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Nov 08, 2019

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The LIFR c.364A>G; p.Thr122Ala variant (rs145163157), to our knowledge, is not reported in the medical literature but is reported in ClinVar (Variation ID: 283380). This variant is found in the African population with an allele frequency of 0.35% (86/24,768 alleles) in the Genome Aggregation Database. The threonine at codon 122 is weakly conserved, and computational algorithms (PolyPhen-2, SIFT) predict that this variant is benign. However, due to limited information, the clinical significance of this variant is uncertain at this time. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.066

BayesDel_addAF

Benign

-0.54

BayesDel_noAF

Benign

-0.54

CADD

Benign

4.3

(source)

DANN

Benign

0.51

DEOGEN2

Benign

0.25

T;T;T

Eigen

Benign

-1.0

Eigen_PC

Benign

-0.97

FATHMM_MKL

Benign

0.029

LIST_S2

Benign

0.49

.;T;T

M_CAP

Benign

0.014

MetaRNN

Benign

0.0052

T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.1

L;L;.

PhyloP100

0.15

PrimateAI

Benign

0.28

PROVEAN

Benign

-0.15

N;N;N

REVEL

Benign

0.017

Sift

Benign

0.47

T;T;T

Sift4G

Benign

0.49

T;T;.

Polyphen

0.0030

B;B;.

Vest4

0.057

MVP

0.42

MPC

0.086

ClinPred

0.0029

GERP RS

-0.20

Varity_R

0.071

gMVP

0.14

Mutation Taster

=97/3

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over