22-30243962-C-T

Variant names:

• chr22-30243962-C-T
• rs769308378
• NM_002309.5:c.298G>A

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_002309.5(LIF):​c.298G>A​(p.Ala100Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000547 in 1,461,850 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A100P) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000055 (0 hom.)
• Consequence: LIF NM_002309.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.21
• Publications: 0 publications found

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

Our verdict: Benign. The variant received -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.05796492).
• BS2: High AC in GnomAdExome4 at 8 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002309.5. 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
	LIF	NM_002309.5	MANE Select	c.298G>A	p.Ala100Thr	missense	Exon 3 of 3	NP_002300.1	P15018-1
	LIF	NM_001257135.2		c.119G>A	p.Gly40Asp	missense	Exon 2 of 2	NP_001244064.1	P15018-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LIF	ENST00000249075.4	TSL:1 MANE Select	c.298G>A	p.Ala100Thr	missense	Exon 3 of 3	ENSP00000249075.3	P15018-1
	LIF	ENST00000403987.3	TSL:1	c.119G>A	p.Gly40Asp	missense	Exon 2 of 2	ENSP00000384450.3	P15018-2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000200 AC: 5 AN: 249884 AF XY: 0.0000296

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.0000993

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000547 AC: 8 AN: 1461850 Hom.: 0 Cov.: 31 AF XY: 0.00000825 AC XY: 6 AN XY: 727226

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44720

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000580 AC: 5 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53388

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1112006

Other (OTH) AF: 0.0000166 AC: 1 AN: 60396

GnomAD4 genome Cov.: 32

Alfa AF: 0.000111 Hom.: 0

ExAC AF: 0.0000247 AC: 3

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.065
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.60
CADD	Benign	18
DANN	Uncertain	0.97
DEOGEN2	Benign	0.31	T
Eigen	Benign	-0.55
Eigen_PC	Benign	-0.39
FATHMM_MKL	Benign	0.59	D
LIST_S2	Benign	0.64	T
M_CAP	Benign	0.0055	T
MetaRNN	Benign	0.058	T
MetaSVM	Benign	-1.0	T
PhyloP100		2.2
PrimateAI	Benign	0.24	T
PROVEAN	Benign	-0.25	N
REVEL	Benign	0.12
Sift	Benign	0.61	T
Sift4G	Benign	0.57	T
Polyphen		0.0	B
Vest4		0.015
MutPred		0.36		Loss of helix (P = 0.0093)
MVP		0.36
MPC		0.33
ClinPred		0.42	T
GERP RS		2.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.11
gMVP		0.19
Mutation Taster		=88/12	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: rs769308378; hg19: chr22-30639951;