chr5-38493772-T-C

Position:

• chr5-38493772-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001127671.2(LIFR):​c.1899A>G​(p.Ile633Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00371 in 1,613,954 control chromosomes in the GnomAD database, including 93 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I633T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0072 (18 hom., cov: 32)
  • Exomes 𝑓: 0.0034 (75 hom.)
• Consequence: LIFR NM_001127671.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -0.102

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=0.0020363927).
• BP6: Variant 5-38493772-T-C is Benign according to our data. Variant chr5-38493772-T-C is described in ClinVar as [Benign]. Clinvar id is 194373.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-38493772-T-C is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00717 (1092/152328) while in subpopulation AMR AF= 0.0336 (515/15306). AF 95% confidence interval is 0.0312. There are 18 homozygotes in gnomad4. There are 610 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 18 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LIFR	NM_001127671.2	c.1899A>G	p.Ile633Met	missense_variant	14/20	ENST00000453190.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LIFR	ENST00000453190.7	c.1899A>G	p.Ile633Met	missense_variant	14/20	2	NM_001127671.2	P1
LIFR	ENST00000263409.8	c.1899A>G	p.Ile633Met	missense_variant	14/20	1		P1
LIFR	ENST00000503088.1	n.2062A>G		non_coding_transcript_exon_variant	14/15	1
LIFR	ENST00000506003.5	c.*77A>G		3_prime_UTR_variant, NMD_transcript_variant	4/7	3

Frequencies

GnomAD3 genomes AF: 0.00718 AC: 1093 AN: 152210 Hom.: 18 Cov.: 32

Gnomad AFR AF: 0.00425

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0337

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0167

Gnomad SAS AF: 0.00103

Gnomad FIN AF: 0.0170

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00171

Gnomad OTH AF: 0.00574

GnomAD3 exomes AF: 0.00893 AC: 2245 AN: 251436 Hom.: 31 AF XY: 0.00754 AC XY: 1024 AN XY: 135886

Gnomad AFR exome AF: 0.00406

Gnomad AMR exome AF: 0.0353

Gnomad ASJ exome AF: 0.0000992

Gnomad EAS exome AF: 0.0145

Gnomad SAS exome AF: 0.000817

Gnomad FIN exome AF: 0.0208

Gnomad NFE exome AF: 0.00131

Gnomad OTH exome AF: 0.0106

GnomAD4 exome AF: 0.00335 AC: 4900 AN: 1461626 Hom.: 75 Cov.: 31 AF XY: 0.00318 AC XY: 2314 AN XY: 727136

Gnomad4 AFR exome AF: 0.00415

Gnomad4 AMR exome AF: 0.0350

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.0273

Gnomad4 SAS exome AF: 0.000730

Gnomad4 FIN exome AF: 0.0199

Gnomad4 NFE exome AF: 0.000670

Gnomad4 OTH exome AF: 0.00383

GnomAD4 genome AF: 0.00717 AC: 1092 AN: 152328 Hom.: 18 Cov.: 32 AF XY: 0.00819 AC XY: 610 AN XY: 74496

Gnomad4 AFR AF: 0.00423

Gnomad4 AMR AF: 0.0336

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.0168

Gnomad4 SAS AF: 0.00104

Gnomad4 FIN AF: 0.0170

Gnomad4 NFE AF: 0.00171

Gnomad4 OTH AF: 0.00568

Alfa AF: 0.00277 Hom.: 3

Bravo AF: 0.00730

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.00431 AC: 19

ESP6500EA AF: 0.000930 AC: 8

ExAC AF: 0.00713 AC: 865

Asia WGS AF: 0.0110 AC: 38 AN: 3478

EpiCase AF: 0.000327

EpiControl AF: 0.000178

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 21, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Jan 05, 2017	- -

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.	Sep 16, 2020	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Jan 06, 2015

- -

Stüve-Wiedemann syndrome 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Nov 08, 2023

- -

Connective tissue disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Oct 01, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.067
BayesDel_addAF	Benign	-0.60	T
BayesDel_noAF	Benign	-0.60
CADD	Benign	10
DANN	Benign	0.79
DEOGEN2	Benign	0.30	T;T
Eigen	Benign	-0.76
Eigen_PC	Benign	-0.63
FATHMM_MKL	Benign	0.73	D
LIST_S2	Benign	0.56	.;T
MetaRNN	Benign	0.0020	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-0.20	N;N
MutationTaster	Benign	0.99	N;N
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-0.27	N;N
REVEL	Benign	0.052
Sift	Benign	0.095	T;T
Sift4G	Benign	0.33	T;T
Polyphen		0.0020	B;B
Vest4		0.097
MVP		0.30
MPC		0.087
ClinPred		0.0037	T
GERP RS		-0.20
Varity_R		0.061
gMVP		0.35

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: rs2303743; hg19: chr5-38493874;