rs3729740

Variant names:

• chr5-38496535-C-T
• rs3729740
• NM_001127671.2:c.1732G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001127671.2(LIFR):​c.1732G>A​(p.Asp578Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00888 in 1,613,952 control chromosomes in the GnomAD database, including 1,472 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 (★★).

• Frequency:
  • Genomes: 𝑓 0.012 (181 hom., cov: 33)
  • Exomes 𝑓: 0.0086 (1291 hom.)
• Consequence: LIFR NM_001127671.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.467
• Publications: 26 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: Orphanet, ClinGen
• 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=0.0016947091).
• BP6: Variant 5-38496535-C-T is Benign according to our data. Variant chr5-38496535-C-T is described in ClinVar as Benign. ClinVar VariationId is 353625.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.237 is higher than 0.05.

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.1732G>A	p.Asp578Asn	missense	Exon 13 of 20	NP_001121143.1	P42702-1
	LIFR	NM_001364297.2		c.1732G>A	p.Asp578Asn	missense	Exon 13 of 20	NP_001351226.1	P42702-1
	LIFR	NM_002310.6		c.1732G>A	p.Asp578Asn	missense	Exon 13 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.1732G>A	p.Asp578Asn	missense	Exon 13 of 20	ENSP00000398368.2	P42702-1
	LIFR	ENST00000263409.8	TSL:1	c.1732G>A	p.Asp578Asn	missense	Exon 13 of 20	ENSP00000263409.4	P42702-1
	LIFR	ENST00000503088.1	TSL:1	n.1895G>A		non_coding_transcript_exon	Exon 13 of 15

Frequencies

GnomAD3 genomes AF: 0.0115 AC: 1752 AN: 152188 Hom.: 180 Cov.: 33

Gnomad AFR AF: 0.00164

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00766

Gnomad ASJ AF: 0.000865

Gnomad EAS AF: 0.248

Gnomad SAS AF: 0.0120

Gnomad FIN AF: 0.0120

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000999

Gnomad OTH AF: 0.0105

GnomAD2 exomes AF: 0.0220 AC: 5533 AN: 251410 AF XY: 0.0207

Gnomad AFR exome AF: 0.00123

Gnomad AMR exome AF: 0.00778

Gnomad ASJ exome AF: 0.000992

Gnomad EAS exome AF: 0.253

Gnomad FIN exome AF: 0.0105

Gnomad NFE exome AF: 0.00110

Gnomad OTH exome AF: 0.0112

GnomAD4 exome AF: 0.00860 AC: 12566 AN: 1461646 Hom.: 1291 Cov.: 32 AF XY: 0.00850 AC XY: 6181 AN XY: 727136

African (AFR) AF: 0.000956 AC: 32 AN: 33476

American (AMR) AF: 0.00812 AC: 363 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.000765 AC: 20 AN: 26134

East Asian (EAS) AF: 0.245 AC: 9727 AN: 39686

South Asian (SAS) AF: 0.00605 AC: 522 AN: 86252

European-Finnish (FIN) AF: 0.00900 AC: 481 AN: 53420

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

European-Non Finnish (NFE) AF: 0.000460 AC: 511 AN: 1111794

Other (OTH) AF: 0.0149 AC: 902 AN: 60392

GnomAD4 genome AF: 0.0116 AC: 1761 AN: 152306 Hom.: 181 Cov.: 33 AF XY: 0.0132 AC XY: 982 AN XY: 74474

African (AFR) AF: 0.00164 AC: 68 AN: 41556

American (AMR) AF: 0.00830 AC: 127 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.000865 AC: 3 AN: 3470

East Asian (EAS) AF: 0.248 AC: 1285 AN: 5186

South Asian (SAS) AF: 0.0124 AC: 60 AN: 4824

European-Finnish (FIN) AF: 0.0120 AC: 127 AN: 10608

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

European-Non Finnish (NFE) AF: 0.000999 AC: 68 AN: 68040

Other (OTH) AF: 0.0109 AC: 23 AN: 2116

Alfa AF: 0.00977 Hom.: 323

Bravo AF: 0.0124

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00136 AC: 6

ESP6500EA AF: 0.00140 AC: 12

ExAC AF: 0.0209 AC: 2541

Asia WGS AF: 0.0970 AC: 337 AN: 3478

EpiCase AF: 0.000600

EpiControl AF: 0.000711

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	2	Stuve-Wiedemann syndrome (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.063
BayesDel_addAF	Benign	-0.77	T
BayesDel_noAF	Benign	-0.73
CADD	Benign	16
DANN	Benign	0.88
DEOGEN2	Benign	0.25	T
Eigen	Benign	-0.97
Eigen_PC	Benign	-0.86
FATHMM_MKL	Benign	0.053	N
LIST_S2	Benign	0.63	T
MetaRNN	Benign	0.0017	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.35	N
PhyloP100		0.47
PrimateAI	Benign	0.28	T
PROVEAN	Benign	0.080	N
REVEL	Benign	0.035
Sift	Benign	0.61	T
Sift4G	Benign	0.92	T
Polyphen		0.0	B
Vest4		0.070
MPC		0.083
ClinPred		0.0048	T
GERP RS		1.9
Varity_R		0.038
gMVP		0.20
Mutation Taster		=99/1	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs3729740; hg19: chr5-38496637; COSMIC: COSV54684844;