22-30244004-C-T

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_002309.5(LIF):c.256G>A(p.Val86Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00661 in 1,613,556 control chromosomes in the GnomAD database, including 46 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/15 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0051 (6 hom., cov: 32)
  • Exomes 𝑓: 0.0068 (40 hom.)
• Consequence: LIF NM_002309.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.663

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]

ACMG classification

Verdict is Benign. Variant got -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.006029725).
• BP6: Variant 22-30244004-C-T is Benign according to our data. Variant chr22-30244004-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 403032.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd at 779 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LIF	NM_002309.5	c.256G>A	p.Val86Met	missense_variant	3/3	ENST00000249075.4
LIF	NM_001257135.2	c.77G>A	p.Arg26His	missense_variant	2/2
LIF	XM_047441361.1	c.574G>A	p.Val192Met	missense_variant	3/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LIF	ENST00000249075.4	c.256G>A	p.Val86Met	missense_variant	3/3	1	NM_002309.5	P1
LIF	ENST00000403987.3	c.77G>A	p.Arg26His	missense_variant	2/2	1

Frequencies

GnomAD3 genomes AF: 0.00512 AC: 779 AN: 152140 Hom.: 6 Cov.: 32

Gnomad AFR AF: 0.00179

Gnomad AMI AF: 0.0296

Gnomad AMR AF: 0.00373

Gnomad ASJ AF: 0.0153

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00352

Gnomad FIN AF: 0.00123

Gnomad MID AF: 0.0285

Gnomad NFE AF: 0.00759

Gnomad OTH AF: 0.00622

GnomAD3 exomes AF: 0.00521 AC: 1295 AN: 248444 Hom.: 4 AF XY: 0.00511 AC XY: 687 AN XY: 134450

Gnomad AFR exome AF: 0.00148

Gnomad AMR exome AF: 0.00335

Gnomad ASJ exome AF: 0.0168

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00261

Gnomad FIN exome AF: 0.00100

Gnomad NFE exome AF: 0.00757

Gnomad OTH exome AF: 0.00653

GnomAD4 exome AF: 0.00677 AC: 9889 AN: 1461298 Hom.: 40 Cov.: 31 AF XY: 0.00666 AC XY: 4841 AN XY: 726916

Gnomad4 AFR exome AF: 0.00134

Gnomad4 AMR exome AF: 0.00351

Gnomad4 ASJ exome AF: 0.0164

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00256

Gnomad4 FIN exome AF: 0.00125

Gnomad4 NFE exome AF: 0.00762

Gnomad4 OTH exome AF: 0.00709

GnomAD4 genome AF: 0.00511 AC: 778 AN: 152258 Hom.: 6 Cov.: 32 AF XY: 0.00506 AC XY: 377 AN XY: 74442

Gnomad4 AFR AF: 0.00178

Gnomad4 AMR AF: 0.00373

Gnomad4 ASJ AF: 0.0153

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00352

Gnomad4 FIN AF: 0.00123

Gnomad4 NFE AF: 0.00759

Gnomad4 OTH AF: 0.00616

Alfa AF: 0.00758 Hom.: 7

Bravo AF: 0.00530

TwinsUK AF: 0.00755 AC: 28

ALSPAC AF: 0.00778 AC: 30

ESP6500AA AF: 0.00136 AC: 6

ESP6500EA AF: 0.0102 AC: 88

ExAC AF: 0.00518 AC: 629

Asia WGS AF: 0.00202 AC: 7 AN: 3478

EpiCase AF: 0.00900

EpiControl AF: 0.00919

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Mar 28, 2016

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: MAF -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Nov 01, 2022

LIF: BP4, BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.56	T
BayesDel_noAF	Benign	-0.50
Cadd	Benign	21
Dann	Benign	0.96
Eigen	Benign	-0.51
Eigen_PC	Benign	-0.41
FATHMM_MKL	Benign	0.30	N
MetaRNN	Benign	0.0060	T
MetaSVM	Benign	-0.95	T
MutationTaster	Benign	1.0	N;N
PROVEAN	Pathogenic	-5.0	D
REVEL	Benign	0.044
Vest4		0.17
MVP		0.32
ClinPred		0.0033	T
GERP RS		3.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0

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: rs41281637; hg19: chr22-30639993; COSMIC: COSV50777277; COSMIC: COSV50777277;