rs2303743

Variant names:

• chr5-38493772-T-C
• rs2303743
• NM_001127671.2:c.1899A>G

Variant summary

Our verdict is Benign. The variant received -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. 16/21 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:9
• Conservation: PhyloP100: -0.102
• Publications: 12 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):

• Stüve-Wiedemann syndrome

  Inheritance: AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
• Stüve-Wiedemann syndrome 1

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -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 VariationId is 194373.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 18 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001127671.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LIFR	NM_001127671.2	MANE Select	c.1899A>G	p.Ile633Met	missense	Exon 14 of 20	NP_001121143.1	P42702-1
	LIFR	NM_001364297.2		c.1899A>G	p.Ile633Met	missense	Exon 14 of 20	NP_001351226.1	P42702-1
	LIFR	NM_002310.6		c.1899A>G	p.Ile633Met	missense	Exon 14 of 20	NP_002301.1	P42702-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LIFR	ENST00000453190.7	TSL:2 MANE Select	c.1899A>G	p.Ile633Met	missense	Exon 14 of 20	ENSP00000398368.2	P42702-1
	LIFR	ENST00000263409.8	TSL:1	c.1899A>G	p.Ile633Met	missense	Exon 14 of 20	ENSP00000263409.4	P42702-1
	LIFR	ENST00000503088.1	TSL:1	n.2062A>G		non_coding_transcript_exon	Exon 14 of 15

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

GnomAD2 exomes AF: 0.00893 AC: 2245 AN: 251436 AF XY: 0.00754

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 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

African (AFR) AF: 0.00415 AC: 139 AN: 33474

American (AMR) AF: 0.0350 AC: 1567 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26136

East Asian (EAS) AF: 0.0273 AC: 1082 AN: 39696

South Asian (SAS) AF: 0.000730 AC: 63 AN: 86256

European-Finnish (FIN) AF: 0.0199 AC: 1064 AN: 53416

Middle Eastern (MID) AF: 0.00139 AC: 8 AN: 5768

European-Non Finnish (NFE) AF: 0.000670 AC: 745 AN: 1111770

Other (OTH) AF: 0.00383 AC: 231 AN: 60386

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

African (AFR) AF: 0.00423 AC: 176 AN: 41564

American (AMR) AF: 0.0336 AC: 515 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.0168 AC: 87 AN: 5190

South Asian (SAS) AF: 0.00104 AC: 5 AN: 4830

European-Finnish (FIN) AF: 0.0170 AC: 181 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00171 AC: 116 AN: 68026

Other (OTH) AF: 0.00568 AC: 12 AN: 2112

Alfa AF: 0.00332 Hom.: 7

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

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	2	Stuve-Wiedemann syndrome (2)
-	-	1	Connective tissue disorder (1)
-	-	1	not specified (1)
-	-	1	Stüve-Wiedemann syndrome 1 (1)

Computational scores

Source: dbNSFP v4.9

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
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
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-0.20	N
PhyloP100		-0.10
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-0.27	N
REVEL	Benign	0.052
Sift	Benign	0.095	T
Sift4G	Benign	0.33	T
Polyphen		0.0020	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
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs2303743; hg19: chr5-38493874;