chr5-38496478-G-A

Position:

chr5-38496478-G-A

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1PM2PP5_Moderate

The NM_001127671.2(LIFR):c.1789C>T(p.Arg597Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000248 in 1,613,890 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 Pathogenic (★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

LIFR
NM_001127671.2 stop_gained

Scores

Clinical Significance

Pathogenic criteria provided, single submitter P:4

Conservation

PhyloP100: 0.807

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 Pathogenic. Variant got 12 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 5-38496478-G-A is Pathogenic according to our data. Variant chr5-38496478-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 14460.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LIFR	NM_001127671.2 linkuse as main transcript	c.1789C>T	p.Arg597Ter	stop_gained	13/20	ENST00000453190.7	NP_001121143.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LIFR	ENST00000453190.7 linkuse as main transcript	c.1789C>T	p.Arg597Ter	stop_gained	13/20	2	NM_001127671.2	ENSP00000398368	P1	P42702-1
LIFR	ENST00000263409.8 linkuse as main transcript	c.1789C>T	p.Arg597Ter	stop_gained	13/20	1		ENSP00000263409	P1	P42702-1
LIFR	ENST00000503088.1 linkuse as main transcript	n.1952C>T		non_coding_transcript_exon_variant	13/15	1
LIFR	ENST00000506003.5 linkuse as main transcript	c.168C>T	p.Tyr56=	synonymous_variant, NMD_transcript_variant	3/7	3		ENSP00000426919

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152154

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

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:

0.00

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

251466

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135904

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1461618

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727148

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000180

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152272

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74452

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000647

Hom.:

Bravo

AF:

0.0000189

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Stuve-Wiedemann syndrome

Pathogenic:3

Pathogenic, no assertion criteria provided	literature only	OMIM	Feb 01, 2004	- -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Jul 08, 2020	- -
Pathogenic, no assertion criteria provided	research	Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine	-	- -

not provided

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 10, 2023

This sequence change creates a premature translational stop signal (p.Arg597*) 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 (rs121912501, gnomAD 0.003%). This premature translational stop signal has been observed in individuals with Stuve-Wiedemann syndrome (PMID: 14740318). ClinVar contains an entry for this variant (Variation ID: 14460). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.56

BayesDel_noAF

Pathogenic

0.28

CADD

Pathogenic

DANN

Uncertain

0.99

Eigen

Uncertain

0.30

Eigen_PC

Benign

-0.010

FATHMM_MKL

Benign

0.29

MutationTaster

Benign

1.0

A;A

Vest4

0.92

GERP RS

1.5

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