5-38475925-T-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_001127671.2(LIFR):c.*5670A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.316 in 192,484 control chromosomes in the GnomAD database, including 10,116 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.31 (7738 hom., cov: 33)
  • Exomes 𝑓: 0.33 (2378 hom.)
• Consequence: LIFR NM_001127671.2 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.353

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.65).
• BP6: Variant 5-38475925-T-C is Benign according to our data. Variant chr5-38475925-T-C is described in ClinVar as [Benign]. Clinvar id is 353531.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.411 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LIFR	NM_001127671.2	c.*5670A>G		3_prime_UTR_variant	20/20	ENST00000453190.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LIFR	ENST00000453190.7	c.*5670A>G		3_prime_UTR_variant	20/20	2	NM_001127671.2	P1
LIFR	ENST00000263409.8	c.*5670A>G		3_prime_UTR_variant	20/20	1		P1

Frequencies

GnomAD3 genomes AF: 0.312 AC: 47432 AN: 151926 Hom.: 7737 Cov.: 33

Gnomad AFR AF: 0.209

Gnomad AMI AF: 0.310

Gnomad AMR AF: 0.381

Gnomad ASJ AF: 0.239

Gnomad EAS AF: 0.426

Gnomad SAS AF: 0.388

Gnomad FIN AF: 0.308

Gnomad MID AF: 0.332

Gnomad NFE AF: 0.350

Gnomad OTH AF: 0.320

GnomAD4 exome AF: 0.330 AC: 13325 AN: 40438 Hom.: 2378 Cov.: 0 AF XY: 0.326 AC XY: 6101 AN XY: 18708

Gnomad4 AFR exome AF: 0.186

Gnomad4 AMR exome AF: 0.337

Gnomad4 ASJ exome AF: 0.225

Gnomad4 EAS exome AF: 0.397

Gnomad4 SAS exome AF: 0.377

Gnomad4 FIN exome AF: 0.326

Gnomad4 NFE exome AF: 0.331

Gnomad4 OTH exome AF: 0.328

GnomAD4 genome AF: 0.312 AC: 47445 AN: 152046 Hom.: 7738 Cov.: 33 AF XY: 0.314 AC XY: 23336 AN XY: 74318

Gnomad4 AFR AF: 0.209

Gnomad4 AMR AF: 0.381

Gnomad4 ASJ AF: 0.239

Gnomad4 EAS AF: 0.426

Gnomad4 SAS AF: 0.388

Gnomad4 FIN AF: 0.308

Gnomad4 NFE AF: 0.350

Gnomad4 OTH AF: 0.320

Alfa AF: 0.341 Hom.: 3541

Bravo AF: 0.311

Asia WGS AF: 0.397 AC: 1377 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Stuve-Wiedemann syndrome Benign:1

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.65
Cadd	Benign	10
Dann	Benign	0.76

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

Other links and lift over

dbSNP: rs3822425; hg19: chr5-38476027; COSMIC: COSV105039490;