5-38481601-G-T

Variant names:

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_001127671.2(LIFR):c.3288C>A(p.Asn1096Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00188 in 1,614,062 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0018 ( 1 hom., cov: 32)

Exomes 𝑓: 0.0019 ( 3 hom. )

Consequence

LIFR
NM_001127671.2 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4B:5

Conservation

PhyloP100: -0.331

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 -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.011234254).

BP6

Variant 5-38481601-G-T is Benign according to our data. Variant chr5-38481601-G-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 353605.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=3}.

BS1

Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00176 (268/152256) while in subpopulation AMR AF= 0.00334 (51/15292). AF 95% confidence interval is 0.00261. There are 1 homozygotes in gnomad4. There are 140 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAdExome4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LIFR	NM_001127671.2 link	c.3288C>A	p.Asn1096Lys	missense_variant	Exon 20 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.3288C>A	p.Asn1096Lys	missense_variant	Exon 20 of 20	2	NM_001127671.2	ENSP00000398368.2		P42702-1
LIFR	ENST00000263409.8 link	c.3288C>A	p.Asn1096Lys	missense_variant	Exon 20 of 20	1		ENSP00000263409.4		P42702-1

Frequencies

GnomAD3 genomes

AF:

0.00176

AC:

268

AN:

152138

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000434

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00334

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000754

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00273

Gnomad OTH

AF:

0.00239

GnomAD3 exomes

AF:

0.00150

AC:

376

AN:

250856

Hom.:

AF XY:

0.00173

AC XY:

235

AN XY:

135836

show subpopulations

Gnomad AFR exome

AF:

0.000316

Gnomad AMR exome

AF:

0.000723

Gnomad ASJ exome

AF:

0.000595

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000924

Gnomad NFE exome

AF:

0.00273

Gnomad OTH exome

AF:

0.00164

GnomAD4 exome

AF:

0.00190

AC:

2771

AN:

1461806

Hom.:

Cov.:

AF XY:

0.00187

AC XY:

1361

AN XY:

727200

show subpopulations

Gnomad4 AFR exome

AF:

0.000568

Gnomad4 AMR exome

AF:

0.000760

Gnomad4 ASJ exome

AF:

0.000804

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00124

Gnomad4 NFE exome

AF:

0.00228

Gnomad4 OTH exome

AF:

0.00166

GnomAD4 genome

AF:

0.00176

AC:

268

AN:

152256

Hom.:

Cov.:

AF XY:

0.00188

AC XY:

140

AN XY:

74442

show subpopulations

Gnomad4 AFR

AF:

0.000433

Gnomad4 AMR

AF:

0.00334

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000754

Gnomad4 NFE

AF:

0.00273

Gnomad4 OTH

AF:

0.00237

Alfa

AF:

0.000192

Hom.:

Bravo

AF:

0.00152

TwinsUK

AF:

0.00108

AC:

ALSPAC

AF:

0.000519

AC:

ExAC

AF:

0.00175

AC:

213

EpiCase

AF:

0.00251

EpiControl

AF:

0.00219

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4Benign:5

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:2

Aug 31, 2020

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; This variant is associated with the following publications: (PMID: 28334964) -

Jan 20, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

LIFR: BS1 -

Stuve-Wiedemann syndrome

Benign:2

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Likely 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Jan 12, 2020

Natera, Inc.

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not specified

Uncertain:1

Jan 11, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: LIFR c.3288C>A (p.Asn1096Lys) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0015 in 250856 control chromosomes. The observed variant frequency is approximately 1.34 fold of the estimated maximal expected allele frequency for a pathogenic variant in LIFR causing Stuve-Wiedemann Syndrome phenotype (0.0011), suggesting that the variant may be benign. c.3288C>A has been reported in the literature in individuals affected with congenital anomalies of the kidneys and urinary tract (Kosfeld_2017). These report(s) do not provide unequivocal conclusions about association of the variant with Stuve-Wiedemann Syndrome. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in >50%-90% of normal activity (Kosfeld_2017). ClinVar contains an entry for this variant (Variation ID: 353605). Based on the evidence outlined above, the variant was classified as VUS-possibly benign. -

Stüve-Wiedemann syndrome 1

Uncertain:1

Apr 14, 2022

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The LIFR c.3288C>A; p.Asn1096Lys variant (rs3729751) is reported in the literature in several individuals affected with urinary tract malformations as well as in a healthy parent (Kosfeld 2017), but it has not, to our knowledge, been reported in association with skeletal dysplasia. This variant is reported with discrepant classifications in the ClinVar database (Variation ID: 353605) and is found in the non-Finnish European population with an allele frequency of 0.28% (363/129,018 alleles) in the Genome Aggregation Database. The asparagine at codon 1096 is moderately conserved, and computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.251). Functional studies suggest the variant protein is expressed in the cell at wildtype levels but may exhibit slightly diminished cell-surface expression, although it is unclear if this difference is clinically significant (Kosfeld 2017). Due to limited information, the clinical significance of the p.Asn1096Lys variant is uncertain at this time. References: Kosfeld et al. Mutations in the leukemia inhibitory factor receptor (LIFR) gene and Lifr deficiency cause urinary tract malformations. Hum Mol Genet. 2017 May 1;26(9):1716-1731. PMID: 28334964. -

Congenital anomaly of kidney and urinary tract

Uncertain:1

Feb 15, 2024

Weber Lab, Hannover Medical School

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: research

- -

LIFR-related disorder

Benign:1

May 10, 2022

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.32

BayesDel_addAF

Benign

-0.38

BayesDel_noAF

Benign

-0.31

CADD

Benign

7.0

DANN

Uncertain

0.99

DEOGEN2

Benign

0.30

T;T

Eigen

Benign

-0.56

Eigen_PC

Benign

-0.71

FATHMM_MKL

Benign

0.28

LIST_S2

Benign

0.81

.;T

M_CAP

Uncertain

0.089

MetaRNN

Benign

0.011

T;T

MetaSVM

Benign

-0.48

MutationAssessor

Uncertain

2.6

M;M

PrimateAI

Uncertain

0.70

PROVEAN

Benign

-1.2

N;N

REVEL

Benign

0.25

Sift

Pathogenic

0.0

D;D

Sift4G

Uncertain

0.030

D;D

Polyphen

1.0

D;D

Vest4

0.36

MutPred

0.16

Gain of methylation at N1096 (P = 0.0076);Gain of methylation at N1096 (P = 0.0076);

MVP

0.48

MPC

0.50

ClinPred

0.051

GERP RS

-7.9

Varity_R

0.25

gMVP

0.46

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