chr5-38481601-G-T

Variant names:

• chr5-38481601-G-T
• rs3729751
• NM_001127671.2:c.3288C>A

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_001127671.2(LIFR):​c.3288C>A​(p.Asn1096Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00188 in 1,614,062 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. N1096N) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0018 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0019 (3 hom.)
• Consequence: LIFR NM_001127671.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:5
• Conservation: PhyloP100: -0.331
• Publications: 8 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.011234254).
• BP6: Variant 5-38481601-G-T is Benign according to our data. Variant chr5-38481601-G-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 353605.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00176 (268/152256) while in subpopulation AMR AF = 0.00334 (51/15292). AF 95% confidence interval is 0.00261. There are 1 homozygotes in GnomAd4. There are 140 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 3 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.3288C>A	p.Asn1096Lys	missense	Exon 20 of 20	NP_001121143.1	P42702-1
	LIFR	NM_001364297.2		c.3288C>A	p.Asn1096Lys	missense	Exon 20 of 20	NP_001351226.1	P42702-1
	LIFR	NM_002310.6		c.3288C>A	p.Asn1096Lys	missense	Exon 20 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.3288C>A	p.Asn1096Lys	missense	Exon 20 of 20	ENSP00000398368.2	P42702-1
	LIFR	ENST00000263409.8	TSL:1	c.3288C>A	p.Asn1096Lys	missense	Exon 20 of 20	ENSP00000263409.4	P42702-1
	LIFR	ENST00000872131.1		c.3288C>A	p.Asn1096Lys	missense	Exon 21 of 21	ENSP00000542190.1

Frequencies

GnomAD3 genomes AF: 0.00176 AC: 268 AN: 152138 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000434

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00334

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000754

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00273

Gnomad OTH AF: 0.00239

GnomAD2 exomes AF: 0.00150 AC: 376 AN: 250856 AF XY: 0.00173

Gnomad AFR exome AF: 0.000316

Gnomad AMR exome AF: 0.000723

Gnomad ASJ exome AF: 0.000595

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000924

Gnomad NFE exome AF: 0.00273

Gnomad OTH exome AF: 0.00164

GnomAD4 exome AF: 0.00190 AC: 2771 AN: 1461806 Hom.: 3 Cov.: 32 AF XY: 0.00187 AC XY: 1361 AN XY: 727200

African (AFR) AF: 0.000568 AC: 19 AN: 33476

American (AMR) AF: 0.000760 AC: 34 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.000804 AC: 21 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00124 AC: 66 AN: 53418

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5768

European-Non Finnish (NFE) AF: 0.00228 AC: 2530 AN: 1111940

Other (OTH) AF: 0.00166 AC: 100 AN: 60392

GnomAD4 genome AF: 0.00176 AC: 268 AN: 152256 Hom.: 1 Cov.: 32 AF XY: 0.00188 AC XY: 140 AN XY: 74442

African (AFR) AF: 0.000433 AC: 18 AN: 41564

American (AMR) AF: 0.00334 AC: 51 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.000754 AC: 8 AN: 10606

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

European-Non Finnish (NFE) AF: 0.00273 AC: 186 AN: 68008

Other (OTH) AF: 0.00237 AC: 5 AN: 2112

Alfa AF: 0.000130 Hom.: 3

Bravo AF: 0.00152

TwinsUK AF: 0.00108 AC: 4

ALSPAC AF: 0.000519 AC: 2

ExAC AF: 0.00175 AC: 213

EpiCase AF: 0.00251

EpiControl AF: 0.00219

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	2	not provided (3)
-	-	2	Stuve-Wiedemann syndrome (2)
-	1	-	Congenital anomaly of kidney and urinary tract (1)
-	-	1	LIFR-related 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	0.32
BayesDel_addAF	Benign	-0.38	T
BayesDel_noAF	Benign	-0.31
CADD	Benign	7.0
DANN	Uncertain	0.99
DEOGEN2	Benign	0.30	T
Eigen	Benign	-0.56
Eigen_PC	Benign	-0.71
FATHMM_MKL	Benign	0.28	N
LIST_S2	Benign	0.81	T
M_CAP	Uncertain	0.089	D
MetaRNN	Benign	0.011	T
MetaSVM	Benign	-0.48	T
MutationAssessor	Uncertain	2.6	M
PhyloP100		-0.33
PrimateAI	Uncertain	0.70	T
PROVEAN	Benign	-1.2	N
REVEL	Benign	0.25
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.030	D
Polyphen		1.0	D
Vest4		0.36
MutPred		0.16		Gain of methylation at N1096 (P = 0.0076)
MVP		0.48
MPC		0.50
ClinPred		0.051	T
GERP RS		-7.9
Varity_R		0.25
gMVP		0.46
Mutation Taster		=11/89	disease causing (ClinVar)

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: rs3729751; hg19: chr5-38481703;