NM_001127671.2:c.1732G>A

Variant names:

• chr5-38496535-C-T
• rs3729740
• NM_001127671.2:c.1732G>A
• LIFR p.Asp578Asn

GermlineCancer (beta)

Variant summary

Our verdict is Benign.

<-10 Benign

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.467
• Publications: 1 publications found

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

Classification according to ACMG Germline Pathogenicity v2019

Classification was made for transcript:

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

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	BP4Computational evidence suggests no impact		Computational evidence supports benign — no pathogenic computational or splicing signal (BP4); Splicing verdict: benign (Strong).; Germline computational verdict: benign (Moderate).
	BP6Reputable source reports benign		ClinVar 2-star benign — strong (BP6); ClinVar germline classification: Benign/Likely Benign, 2 star(s).
	BA1Stand-alone benign allele frequency (>5%)		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

Sel.	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	Prot: NP_001121143.1 UniProt:
	LIFR NM_001364297.2		c.1732G>A p.Asp578Asn	missense	Exon 13 of 20	Prot: NP_001351226.1 UniProt:
	LIFR NM_002310.6		c.1732G>A p.Asp578Asn	missense	Exon 13 of 20	Prot: NP_002301.1 UniProt:

LIFR NM_001127671.2

MANE Select

HGVSc / HGVSpc.1732G>Ap.Asp578Asn

Exon rankExon 13 of 20

missense

Prot: NP_001121143.1UniProt: P42702-1

LIFR NM_001364297.2

HGVSc / HGVSpc.1732G>Ap.Asp578Asn

Exon rankExon 13 of 20

missense

Prot: NP_001351226.1UniProt: P42702-1

LIFR NM_002310.6

HGVSc / HGVSpc.1732G>Ap.Asp578Asn

Exon rankExon 13 of 20

missense

Prot: NP_002301.1UniProt: P42702-1

Ensembl Transcripts

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

LIFR ENST00000453190.7

TSL:2MANE Select

HGVSc / HGVSpc.1732G>Ap.Asp578Asn

Exon rankExon 13 of 20

missense

Prot: ENSP00000398368.2UniProt: P42702

LIFR ENST00000263409.8

TSL:1

HGVSc / HGVSpc.1732G>Ap.Asp578Asn

Exon rankExon 13 of 20

missense

Prot: ENSP00000263409.4UniProt: P42702

LIFR ENST00000503088.1

TSL:1

HGVSc / HGVSpn.1895G>A

Exon rankExon 13 of 15

non_coding_transcript_exon

Prot:

Frequencies

Allele frequencies (AF), counts (AC/AN), homozygotes and coverage

Common (AF > 0.05 / Hom > 5)

Rare (AF ≤ 0.0001 / Hom ≤ 1)

Source / population	AF	AC	Hom	AN	Coverage
Global population databases 6 sources Large-scale international reference populations
GnomAD3 genomes	AF: 0.0115	AC:1752	Hom:180	AN:152188	Cov:33
GnomAD2 exomes	AF: 0.0220	AC:5533	Hom:	AN:251410	Cov:
GnomAD4 exome	AF: 0.00860	AC:12566	Hom:1291	AN:1461646	Cov:32
GnomAD4 genome	AF: 0.0116	AC:1761	Hom:181	AN:152306	Cov:33
TOPMed (Bravo)	AF: 0.0124	AC:	Hom:	AN:	Cov:
ALFA (dbGaP/dbSNP Allele Frequency Aggregator)	AF: 0.00896	AC:3230	Hom:324	AN:360380	Cov:
Local & regional cohorts 10 sources Population-specific and national genomic databases
ABraOM SABE-WGS-1171	AF: 0.0145	AC:34	Hom:4	AN:2342	Cov:
ChinaMAP Phase 1	AF: 0.255	AC:	Hom:	AN:	Cov:
ESP6500 (Exome Variant Server)	AF: 0.00138	AC:18	Hom:	AN:13006	Cov:
GenomeAsia100K	AF: 0.0970	AC:337	Hom:	AN:3478	Cov:
Korea4K (4,157 Koreans)	AF: 0.234	AC:1695	Hom:	AN:7234	Cov:
Qatari Genome	AF: 0.00120	AC:2	Hom:	AN:1706	Cov:
ToMMo 61KJPN (+60KJPN MNV)	AF: 0.239	AC:29363	Hom:3586	AN:122820	Cov:
Turkish Variome	AF: 0.0128	AC:86	Hom:2	AN:6720	Cov:
UK10K	AF: 0.000132	AC:1	Hom:	AN:7562	Cov:
WBBC (Westlake BioBank for Chinese) pilot	AF: 0.258	AC:2313	Hom:290	AN:8960	Cov:

Showing 16 sources

Case/control cohorts

Cohort	Cases			Controls
	AF	AC	AN	AF	AC	AN
ASC(Autism)	0.00104 *	10	9622	0.00105 *	11	10428
BipEx(Bipolar disorder (including schizoaffective))	0.00116	33	28420	0.00149	43	28844
Epi25(Epilepsy)	0.0217	912	41958	0.0111	741	66888
SCHEMA(Schizophrenia)	0.0726	9500	130806	0.0515	10303	200008

Showing 4 cohortsAllele 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

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	2	Stuve-Wiedemann syndrome (2)

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Uncertain	17
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
Eigen	Benign	-0.97
Eigen_PC	Benign	-0.86
FATHMM_MKL	Benign	0.053	N
FuncVEP CTI	Benign	0.00072
GPN-Star LLR	N/A	-3.2
GPN-Star score	N/A	3.2
LIST_S2	Benign	0.63	T
MetaRNN	Benign	0.0017	T
MetaSVM	Benign	-1.0	T
Mutation Taster	N/A	99/1	polymorphism (auto)
MutationAssessor	Benign	-0.35	N
PhyloP100	Benign	0.47
popEVE	Benign	-2.7
PrimateAI	Benign	0.28	T
PROVEAN	Benign	0.080	N
REVEL	Benign	0.035
Sift	Benign	0.61	T
Sift4G	Benign	0.92	T
Varity_R	N/A	0.038
VESM-3B	Benign	-3.9

Showing 27 of 27 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
Pangolin (max)	Benign	0.010
SpliceAI score (max)	Benign	0.020	Details are displayed if max score is > 0.2

Showing 2 of 2 scores

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.

MaveDB functional evidence

MaveDB is a public repository of laboratory assays that test the effect of thousands of variants at once — treat this as supporting research data and interpret it with great caution; it is not a clinical classification.

No MaveDB functional evidence found for this variant.

Other links and lift over

dbSNP: rs3729740;

hg19: chr5-38496637;

COSMIC: COSV54684844;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar