5-38502658-GT-G

Position:

• chr5-38502658-GT-G

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_001127671.2(LIFR):​c.1578del​(p.Lys526AsnfsTer4) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,894 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: LIFR NM_001127671.2 frameshift
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: -0.195

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 Pathogenic. Variant got 18 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 5-38502658-GT-G is Pathogenic according to our data. Variant chr5-38502658-GT-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 506000.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LIFR	NM_001127671.2	c.1578del	p.Lys526AsnfsTer4	frameshift_variant	11/20	ENST00000453190.7	NP_001121143.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LIFR	ENST00000453190.7	c.1578del	p.Lys526AsnfsTer4	frameshift_variant	11/20	2	NM_001127671.2	ENSP00000398368	P1
LIFR	ENST00000263409.8	c.1578del	p.Lys526AsnfsTer4	frameshift_variant	11/20	1		ENSP00000263409	P1
LIFR	ENST00000503088.1	n.1741del		non_coding_transcript_exon_variant	11/15	1
LIFR	ENST00000506003.5	c.17del	p.Lys6AsnfsTer4	frameshift_variant, NMD_transcript_variant	1/7	3		ENSP00000426919

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460894 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 726826

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: 9.00e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Stuve-Wiedemann syndrome Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Sep 26, 2017

The p.Lys526AsnfsX4 (NM_002310.5 c.1578delA) variant in LIFR has not been previo usly reported in individuals with Stuve-Wiedemann syndrome and was absent from l arge population studies. This variant is predicted to cause a frameshift, which alters the protein?s amino acid sequence beginning at position 526 and leads to a premature termination codon 4 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Biallelic loss of function o f the LIFR gene has been associated with Stuve-Wiedemann syndrome. In summary, a lthough additional studies are required to fully establish its clinical signific ance, the p.Lys526AsnfsX4 variant is likely pathogenic for Stuve-Wiedemann syndr ome in an autosomal recessive manner based on a predicted null effect. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

May 23, 2023

For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 506000). This variant has not been reported in the literature in individuals affected with LIFR-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Lys526Asnfs*4) 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). -

Computational scores

Source: dbNSFP v4.3

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr5-38502760;