NM_001127671.2:c.1732_1734delGATinsAAC

Variant names:

• chr5-38496533-ATC-GTT
• NM_001127671.2:c.1732_1734delGATinsAAC
• LIFR p.Asp578Asn

GermlineCancer (beta)

Variant summary

Our verdict is Uncertain significance.

+2 Uncertain · Warm

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received 2 classification points (ACMG Germline Pathogenicity v2019). PM2

The NM_001127671.2(LIFR):c.1732_1734delGATinsAAC (p.Asp578Asn) variant causes a missense change. Note: allele frequency estimates from gnomAD may be inaccurate for this variant type (MNP or indel longer than 3 bp) due to technology limitations. The variant is absent from the gnomAD population database at sites with sufficient sequencing coverage. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Other variants at the same amino acid position have been reported in ClinVar (not pathogenic): p.D578N: Benign (ClinVar VariationId 353625, 2 stars) 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: not found (cov: 33)
• Consequence: LIFR NM_001127671.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.467
• Publications: 0 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: Uncertain_significance. The variant received 2 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	PM2Absent/extremely low in population databases		Absent from gnomAD (AD/XL gene) — PM2; Absent from gnomAD at well-covered site (MOI: AD+AR) (threshold 0.0001) — PM2 moderate.

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.1732_1734delGATinsAAC p.Asp578Asn	missense	N/A	Prot: NP_001121143.1 UniProt:
	LIFR NM_001364297.2		c.1732_1734delGATinsAAC p.Asp578Asn	missense	N/A	Prot: NP_001351226.1 UniProt:
	LIFR NM_002310.6		c.1732_1734delGATinsAAC p.Asp578Asn	missense	N/A	Prot: NP_002301.1 UniProt:

LIFR NM_001127671.2

MANE Select

HGVSc / HGVSpc.1732_1734delGATinsAACp.Asp578Asn

Exon rankN/A

missense

Prot: NP_001121143.1UniProt: P42702-1

LIFR NM_001364297.2

HGVSc / HGVSpc.1732_1734delGATinsAACp.Asp578Asn

Exon rankN/A

missense

Prot: NP_001351226.1UniProt: P42702-1

LIFR NM_002310.6

HGVSc / HGVSpc.1732_1734delGATinsAACp.Asp578Asn

Exon rankN/A

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.1732_1734delGATinsAAC p.Asp578Asn	missense	N/A	Prot: ENSP00000398368.2 UniProt:
	LIFR ENST00000263409.8	TSL:1	c.1732_1734delGATinsAAC p.Asp578Asn	missense	N/A	Prot: ENSP00000263409.4 UniProt:
	LIFR ENST00000503088.1	TSL:1	n.1895_1897delGATinsAAC	non_coding_transcript_exon	Exon 13 of 15	Prot:

LIFR ENST00000453190.7

TSL:2MANE Select

HGVSc / HGVSpc.1732_1734delGATinsAACp.Asp578Asn

Exon rankN/A

missense

Prot: ENSP00000398368.2UniProt: P42702

LIFR ENST00000263409.8

TSL:1

HGVSc / HGVSpc.1732_1734delGATinsAACp.Asp578Asn

Exon rankN/A

missense

Prot: ENSP00000263409.4UniProt: P42702

LIFR ENST00000503088.1

TSL:1

HGVSc / HGVSpn.1895_1897delGATinsAAC

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 2 sources Large-scale international reference populations
GnomAD3 genomes	AF:	AC:	Hom:	AN:	Cov:33
GnomAD4 genome	AF:	AC:	Hom:	AN:	Cov:33

Showing 2 sources

ClinVar

Not reported in ClinVar

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
PhyloP100	Benign	0.47

Showing 1 of 1 scores

Splicing Scores

No splicing scores have been computed for this variant.

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

hg19: chr5-38496635;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar