rs3729740

chr5-38496535-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

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 frequency of 0.00888 in 1,613,952 control chromosomes in the GnomAD database, including 1,472 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.012 (181 hom., cov: 33)
  • Exomes 𝑓: 0.0086 (1291 hom.)
• Consequence: LIFR NM_001127671.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.467

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0016947091).
• BP6: Variant 5-38496535-C-T is Benign according to our data. Variant chr5-38496535-C-T is described in ClinVar as [Benign]. Clinvar id is 353625.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-38496535-C-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.237 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LIFR	NM_001127671.2	c.1732G>A	p.Asp578Asn	missense_variant	13/20	ENST00000453190.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LIFR	ENST00000453190.7	c.1732G>A	p.Asp578Asn	missense_variant	13/20	2	NM_001127671.2	P1
LIFR	ENST00000263409.8	c.1732G>A	p.Asp578Asn	missense_variant	13/20	1		P1
LIFR	ENST00000503088.1	n.1895G>A		non_coding_transcript_exon_variant	13/15	1
LIFR	ENST00000506003.5	c.111-1G>A		splice_acceptor_variant, NMD_transcript_variant		3

Frequencies

GnomAD3 genomes AF: 0.0115 AC: 1752 AN: 152188 Hom.: 180 Cov.: 33

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

GnomAD3 exomes AF: 0.0220 AC: 5533 AN: 251410 Hom.: 601 AF XY: 0.0207 AC XY: 2814 AN XY: 135872

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 SAS exome AF: 0.00532

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.: 32 AF XY: 0.00850 AC XY: 6181 AN XY: 727136

Gnomad4 AFR exome AF: 0.000956

Gnomad4 AMR exome AF: 0.00812

Gnomad4 ASJ exome AF: 0.000765

Gnomad4 EAS exome AF: 0.245

Gnomad4 SAS exome AF: 0.00605

Gnomad4 FIN exome AF: 0.00900

Gnomad4 NFE exome AF: 0.000460

Gnomad4 OTH exome AF: 0.0149

GnomAD4 genome AF: 0.0116 AC: 1761 AN: 152306 Hom.: 181 Cov.: 33 AF XY: 0.0132 AC XY: 982 AN XY: 74474

Gnomad4 AFR AF: 0.00164

Gnomad4 AMR AF: 0.00830

Gnomad4 ASJ AF: 0.000865

Gnomad4 EAS AF: 0.248

Gnomad4 SAS AF: 0.0124

Gnomad4 FIN AF: 0.0120

Gnomad4 NFE AF: 0.000999

Gnomad4 OTH AF: 0.0109

Alfa AF: 0.00971 Hom.: 260

Bravo AF: 0.0124

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00136 AC: 6

ESP6500EA AF: 0.00140 AC: 12

ExAC AF: 0.0209 AC: 2541

Asia WGS AF: 0.0970 AC: 337 AN: 3478

EpiCase AF: 0.000600

EpiControl AF: 0.000711

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Stuve-Wiedemann syndrome Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	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 benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Dec 02, 2019	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 29, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.063
BayesDel_addAF	Benign	-0.77	T
BayesDel_noAF	Benign	-0.73
Cadd	Benign	16
Dann	Benign	0.88
DEOGEN2	Benign	0.25	T;T
Eigen	Benign	-0.97
Eigen_PC	Benign	-0.86
FATHMM_MKL	Benign	0.053	N
MetaRNN	Benign	0.0017	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.35	N;N
MutationTaster	Benign	1.0	P;P
PrimateAI	Benign	0.28	T
PROVEAN	Benign	0.080	N;N
REVEL	Benign	0.035
Sift	Benign	0.61	T;T
Sift4G	Benign	0.92	T;T
Polyphen		0.0	B;B
Vest4		0.070
MPC		0.083
ClinPred		0.0048	T
GERP RS		1.9
Varity_R		0.038
gMVP		0.20

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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

Other links and lift over

dbSNP: rs3729740; hg19: chr5-38496637; COSMIC: COSV54684844;