Variant chr22-30243785-A-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 1P and 4B. PP3BS2

The NM_002309.5(LIF):c.475T>C(p.Tyr159His) variant causes a missense change. The variant allele was found at a frequency of 0.0000294 in 1,461,890 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.000029 ( 0 hom. )

Consequence

LIF
NM_002309.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.45

Variant links:

Genes affected

LIF (HGNC:6596): (LIF interleukin 6 family cytokine) The protein encoded by this gene is a pleiotropic cytokine with roles in several different systems. It is involved in the induction of hematopoietic differentiation in normal and myeloid leukemia cells, induction of neuronal cell differentiation, regulator of mesenchymal to epithelial conversion during kidney development, and may also have a role in immune tolerance at the maternal-fetal interface. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene. [provided by RefSeq, Mar 2012]

LIF links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -3 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.814

BS2

High AC in GnomAdExome4 at 43 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LIF	NM_002309.5 linkuse as main transcript	c.475T>C	p.Tyr159His	missense_variant	3/3	ENST00000249075.4	NP_002300.1	P15018-1
LIF	XM_047441361.1 linkuse as main transcript	c.793T>C	p.Tyr265His	missense_variant	3/3		XP_047297317.1
LIF	NM_001257135.2 linkuse as main transcript	c.*29T>C		3_prime_UTR_variant	2/2		NP_001244064.1	P15018-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LIF	ENST00000249075.4 linkuse as main transcript	c.475T>C	p.Tyr159His	missense_variant	3/3	1	NM_002309.5	ENSP00000249075.3		P15018-1
LIF	ENST00000403987 linkuse as main transcript	c.*29T>C		3_prime_UTR_variant	2/2	1		ENSP00000384450.3		P15018-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000199

AC:

AN:

251472

Hom.:

AF XY:

0.0000221

AC XY:

AN XY:

135908

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.0000992

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000264

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000294

AC:

AN:

1461890

Hom.:

Cov.:

AF XY:

0.0000399

AC XY:

AN XY:

727244

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000306

Gnomad4 OTH exome

AF:

0.0000828

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000658

Hom.:

Bravo

AF:

0.0000113

ExAC

AF:

0.0000247

AC:

EpiCase

AF:

0.000218

EpiControl

AF:

0.000119

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 21, 2022

The c.475T>C (p.Y159H) alteration is located in exon 3 (coding exon 3) of the LIF gene. This alteration results from a T to C substitution at nucleotide position 475, causing the tyrosine (Y) at amino acid position 159 to be replaced by a histidine (H). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.69

BayesDel_addAF

Uncertain

0.072

BayesDel_noAF

Uncertain

-0.040

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.81

Eigen

Uncertain

0.66

Eigen_PC

Uncertain

0.62

FATHMM_MKL

Uncertain

0.86

LIST_S2

Benign

0.68

M_CAP

Uncertain

0.12

MetaRNN

Pathogenic

0.81

MetaSVM

Uncertain

0.26

MutationAssessor

Benign

1.9

PrimateAI

Pathogenic

0.80

PROVEAN

Uncertain

-2.8

REVEL

Pathogenic

0.70

Sift

Benign

0.15

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.62

MVP

0.78

MPC

1.3

ClinPred

0.86

GERP RS

5.0

Varity_R

0.37

gMVP

0.56

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over