rs3729740

Variant names:

Variant summary

Our verdict is The variant received -14 classification points (ACMG Germline Pathogenicity v2019). BA1BP4_ModerateBP6_Strong

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 cumulative frequency of 0.00888 (AC=14,327) in the gnomAD database across 1,613,952 control chromosomes, including 1,472 homozygotes. The grpmax filtering allele frequency (95% CI) is 0.241. In-silico predictor (REVEL) classifies this variant as likely benign. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign/Likely Benign (★★). This exact variant is curated in the UniProt human variants database as Uncertain Significance; it is also listed as a COSMIC curated somatic variant.

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

Publications

26 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):

Stuve-Wiedemann syndrome
Inheritance: AR Classification: DEFINITIVE Submitted by: Natera
Stüve-Wiedemann syndrome
Inheritance: AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
Stüve-Wiedemann syndrome 1
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P, PanelApp Australia
congenital anomaly of kidney and urinary tract
Inheritance: Unknown, AD Classification: STRONG, LIMITED Submitted by: Natera, PanelApp Australia

LIFR links:

Genome browser will be placed here

new If you want to explore the variant's impact on the transcript NM_001127671.2, check out the Mutation Effect Viewer. This is especially useful for frameshift variants or if you want to visualize the effect of exon loss / intron retention.

Classification according to ACMG Germline Pathogenicity v2019

Classification was made for transcript

Our verdict: Benign. The variant received -14 points.

BP4

Computational evidence supports benign — no pathogenic computational or splicing signal (BP4); Splicing verdict: benign (Strong).; Germline computational verdict: benign (Moderate).

BP6

ClinVar 2-star benign — strong (BP6); ClinVar germline classification: Benign/Likely Benign, 2 star(s).

BA1

GnomAD effective popmax AF >5% — BA1 stand-alone benign; GnomAD reliable popmax AF = 0.2410 — exceeds 5%% threshold (BA1 applied)

Variant Effect in Transcripts

Automated classification analysis was done for transcript: NM_001127671.2. You can select a different transcript below to see updated classification assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
LIFR	NM_001127671.2	MANE Select	c.1732G>A	p.Asp578Asn	missense	Exon 13 of 20	NP_001121143.1	P42702-1
LIFR	NM_001364297.2		c.1732G>A	p.Asp578Asn	missense	Exon 13 of 20	NP_001351226.1	P42702-1
LIFR	NM_002310.6		c.1732G>A	p.Asp578Asn	missense	Exon 13 of 20	NP_002301.1	P42702-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
LIFR	ENST00000453190.7	TSL:2 MANE Select	c.1732G>A	p.Asp578Asn	missense	Exon 13 of 20	ENSP00000398368.2	P42702
LIFR	ENST00000263409.8	TSL:1	c.1732G>A	p.Asp578Asn	missense	Exon 13 of 20	ENSP00000263409.4	P42702
LIFR	ENST00000503088.1	TSL:1	n.1895G>A		non_coding_transcript_exon	Exon 13 of 15

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

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.486

Heterozygous variant carriers

670

1341

2011

2682

3352

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

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

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.495

Heterozygous variant carriers

143

214

286

357

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

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

TOPMed (Bravo)

AF:

0.0124

ALFA (dbGaP/dbSNP Allele Frequency Aggregator)

AF:

0.00896

AC:

3230

AN:

360380

Hom.:

324

Local populations

ABraOM SABE-WGS-1171

AF:

0.0145

AC:

AN:

2342

Hom.:

ChinaMAP Phase 1

AF:

0.255

ESP6500 (Exome Variant Server)

AF:

0.00138

AC:

AN:

13006

show subpopulations

European American

AF:

0.00140

AC:

AN:

8600

African American

AF:

0.00136

AC:

AN:

4406

GenomeAsia100K

AF:

0.0970

AC:

337

AN:

3478

show subpopulations

Oceania

AF:

0.0946

AC:

AN:

148

Hom.:

North-East Asia

AF:

0.236

AC:

166

AN:

702

Hom.:

South-East Asia

AF:

0.145

AC:

100

AN:

692

Hom.:

South Asia

AF:

0.0345

AC:

AN:

1448

Hom.:

Africa

AF:

0.00

AC:

AN:

208

Hom.:

America

AF:

0.0769

AC:

AN:

Hom.:

West Eurasia

AF:

0.0132

AC:

AN:

228

Hom.:

Korea4K (4,157 Koreans)

AF:

0.234

AC:

1695

AN:

7234

Qatari Genome

AF:

0.00120

AC:

AN:

1706

ToMMo 61KJPN (+60KJPN MNV)

AF:

0.239

AC:

29363

AN:

122820

Hom.:

3586

Turkish Variome

AF:

0.0128

AC:

AN:

6720

Hom.:

UK10K

AF:

0.000132

AC:

AN:

7562

show subpopulations

TwinsUK

AF:

0.00

AC:

AN:

3574

ALSPAC

AF:

0.000259

AC:

AN:

3854

WBBC (Westlake BioBank for Chinese) pilot

AF:

0.258

AC:

2313

AN:

8960

Hom.:

290

Case/control cohorts

Cohort

Cases

Controls

ASC

(Autism)

10 / 9622AF: 0.00103928

11 / 10428AF: 0.00105485

BipEx

(Bipolar disorder (including schizoaffective))

33 / 28420AF: 0.00116115

43 / 28844AF: 0.00149078

Epi25

(Epilepsy)

912 / 41958AF: 0.0217360

741 / 66888AF: 0.0110782

SCHEMA

(Schizophrenia)

9500 / 130806AF: 0.0726266

10303 / 200008AF: 0.0515129

Allele count / allele number. AF is computed from the counts for ASC (not provided by the source).

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

Stuve-Wiedemann syndrome (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.063

BayesDel_addAF

Benign

-0.77

BayesDel_noAF

Benign

-0.73

CADD

Benign

(source)

DANN

Benign

0.88

DEOGEN2

Benign

0.25

Eigen

Benign

-0.97

Eigen_PC

Benign

-0.86

FATHMM_MKL

Benign

0.053

LIST_S2

Benign

0.63

MetaRNN

Benign

0.0017

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-0.35

PhyloP100

0.47

PrimateAI

Benign

0.28

PROVEAN

Benign

0.080

REVEL

Benign

0.035

Sift

Benign

0.61

Sift4G

Benign

0.92

Varity_R

0.038

popEVE

Benign

-2.7

(source)

VESM-3B

Benign

-3.9

(source)

FuncVEP CTI

Benign

0.00072

(source)

AlphaGenome AVI

Uncertain

(source)

GPN-Star LLR

-3.2

(source)

GPN-Star score

3.2

(source)

Mutation Taster

=99/1

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

Details are displayed if max score is > 0.2

Pangolin (max)

Benign

0.010

(source)

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

Classification according to ACMG Germline Pathogenicity v2019

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

Local populations

Case/control cohorts

ClinVar

Computational scores

Splicing

Publications

Other links and lift over