Genetic Variant CSF2:p.Ile117Thr (chr5-132075767-T-C) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_000758.4(CSF2):c.350T>C(p.Ile117Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.231 in 1,607,090 control chromosomes in the GnomAD database, including 47,794 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 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 nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt.

Frequency

Genomes: 𝑓 0.26 ( 5821 hom., cov: 33)

Exomes 𝑓: 0.23 ( 41973 hom. )

Consequence

CSF2
NM_000758.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.471

Variant links:

Genes affected

CSF2 (HGNC:2434): (colony stimulating factor 2) The protein encoded by this gene is a cytokine that controls the production, differentiation, and function of granulocytes and macrophages. The active form of the protein is found extracellularly as a homodimer. This gene has been localized to a cluster of related genes at chromosome region 5q31, which is known to be associated with interstitial deletions in the 5q- syndrome and acute myelogenous leukemia. Other genes in the cluster include those encoding interleukins 4, 5, and 13. This gene plays a role in promoting tissue inflammation. Elevated levels of cytokines, including the one produced by this gene, have been detected in SARS-CoV-2 infected patients that develop acute respiratory distress syndrome. Mice deficient in this gene or its receptor develop pulmonary alveolar proteinosis. [provided by RefSeq, Aug 2020]

CSF2 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=1.9731318E-5).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.594 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CSF2	NM_000758.4 link	c.350T>C	p.Ile117Thr	missense_variant	Exon 4 of 4	ENST00000296871.4	NP_000749.2	P04141

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CSF2	ENST00000296871.4 link	c.350T>C	p.Ile117Thr	missense_variant	Exon 4 of 4	1	NM_000758.4	ENSP00000296871.2		P04141

Frequencies

GnomAD3 genomes

AF:

0.262

AC:

39826

AN:

152022

Hom.:

5817

Cov.:

show subpopulations

Gnomad AFR

AF:

0.306

Gnomad AMI

AF:

0.158

Gnomad AMR

AF:

0.222

Gnomad ASJ

AF:

0.276

Gnomad EAS

AF:

0.612

Gnomad SAS

AF:

0.262

Gnomad FIN

AF:

0.344

Gnomad MID

AF:

0.250

Gnomad NFE

AF:

0.206

Gnomad OTH

AF:

0.247

GnomAD3 exomes

AF:

0.265

AC:

65402

AN:

247098

Hom.:

10131

AF XY:

0.258

AC XY:

34537

AN XY:

133938

show subpopulations

Gnomad AFR exome

AF:

0.314

Gnomad AMR exome

AF:

0.246

Gnomad ASJ exome

AF:

0.273

Gnomad EAS exome

AF:

0.607

Gnomad SAS exome

AF:

0.236

Gnomad FIN exome

AF:

0.329

Gnomad NFE exome

AF:

0.206

Gnomad OTH exome

AF:

0.245

GnomAD4 exome

AF:

0.228

AC:

331618

AN:

1454950

Hom.:

41973

Cov.:

AF XY:

0.228

AC XY:

164856

AN XY:

724190

show subpopulations

Gnomad4 AFR exome

AF:

0.309

Gnomad4 AMR exome

AF:

0.243

Gnomad4 ASJ exome

AF:

0.272

Gnomad4 EAS exome

AF:

0.595

Gnomad4 SAS exome

AF:

0.235

Gnomad4 FIN exome

AF:

0.323

Gnomad4 NFE exome

AF:

0.205

Gnomad4 OTH exome

AF:

0.247

GnomAD4 genome

AF:

0.262

AC:

39843

AN:

152140

Hom.:

5821

Cov.:

AF XY:

0.269

AC XY:

19975

AN XY:

74376

show subpopulations

Gnomad4 AFR

AF:

0.306

Gnomad4 AMR

AF:

0.222

Gnomad4 ASJ

AF:

0.276

Gnomad4 EAS

AF:

0.612

Gnomad4 SAS

AF:

0.262

Gnomad4 FIN

AF:

0.344

Gnomad4 NFE

AF:

0.206

Gnomad4 OTH

AF:

0.255

Alfa

AF:

0.231

Hom.:

6917

Bravo

AF:

0.258

TwinsUK

AF:

0.201

AC:

745

ALSPAC

AF:

0.199

AC:

766

ESP6500AA

AF:

0.319

AC:

1407

ESP6500EA

AF:

0.212

AC:

1824

ExAC

AF:

0.263

AC:

31920

Asia WGS

AF:

0.445

AC:

1550

AN:

3478

EpiCase

AF:

0.200

EpiControl

AF:

0.198

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.81

BayesDel_noAF

Benign

-0.79

CADD

Benign

0.52

DANN

Benign

0.89

DEOGEN2

Benign

0.33

Eigen

Benign

-1.0

Eigen_PC

Benign

-1.0

FATHMM_MKL

Benign

0.031

LIST_S2

Benign

0.43

MetaRNN

Benign

0.000020

MetaSVM

Benign

-0.93

MutationAssessor

Benign

0.76

PrimateAI

Benign

0.43

PROVEAN

Benign

-0.81

REVEL

Benign

0.035

Sift

Benign

0.68

Sift4G

Benign

0.54

Polyphen

0.0

Vest4

0.017

MPC

0.40

ClinPred

0.00059

GERP RS

-1.5

Varity_R

0.21

gMVP

0.054

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

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

Computational scores

Splicing

Publications

LitVar

Other links and lift over