Genetic Variant NM_000758.4:c.344C>T (chr5-132075761-C-T) – ACMG Classification: Benign (-16 pts)

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2

The NM_000758.4(CSF2):c.344C>T(p.Thr115Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00149 in 1,608,986 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0014 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0015 ( 6 hom. )

Consequence

CSF2
NM_000758.4 missense

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 0.0440

Publications

12 publications found

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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -16 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.007443011).

BP6

Variant 5-132075761-C-T is Benign according to our data. Variant chr5-132075761-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 710325.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High AC in GnomAd4 at 209 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000758.4. 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
	CSF2	NM_000758.4	MANE Select	c.344C>T	p.Thr115Ile	missense	Exon 4 of 4	NP_000749.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CSF2	ENST00000296871.4	TSL:1 MANE Select	c.344C>T	p.Thr115Ile	missense	Exon 4 of 4	ENSP00000296871.2	P04141

Frequencies

GnomAD3 genomes

AF:

0.00137

AC:

209

AN:

152176

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000193

Gnomad AMI

AF:

0.00439

Gnomad AMR

AF:

0.00314

Gnomad ASJ

AF:

0.00490

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000189

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00187

Gnomad OTH

AF:

0.00144

GnomAD2 exomes

AF:

0.00128

AC:

317

AN:

246826

AF XY:

0.00117

show subpopulations

Gnomad AFR exome

AF:

0.000311

Gnomad AMR exome

AF:

0.00130

Gnomad ASJ exome

AF:

0.00567

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000330

Gnomad NFE exome

AF:

0.00170

Gnomad OTH exome

AF:

0.00197

GnomAD4 exome

AF:

0.00150

AC:

2183

AN:

1456692

Hom.:

Cov.:

AF XY:

0.00145

AC XY:

1049

AN XY:

724968

show subpopulations

African (AFR)

AF:

0.000269

AC:

AN:

33466

American (AMR)

AF:

0.00125

AC:

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.00651

AC:

170

AN:

26122

East Asian (EAS)

AF:

0.00

AC:

AN:

39686

South Asian (SAS)

AF:

0.0000580

AC:

AN:

86244

European-Finnish (FIN)

AF:

0.000225

AC:

AN:

48906

Middle Eastern (MID)

AF:

0.000347

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.00162

AC:

1801

AN:

1111448

Other (OTH)

AF:

0.00214

AC:

129

AN:

60334

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.408

Heterozygous variant carriers

184

275

367

459

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

156

234

312

390

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00137

AC:

209

AN:

152294

Hom.:

Cov.:

AF XY:

0.00132

AC XY:

AN XY:

74458

show subpopulations

African (AFR)

AF:

0.000193

AC:

AN:

41554

American (AMR)

AF:

0.00314

AC:

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.00490

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5188

South Asian (SAS)

AF:

0.00

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.000189

AC:

AN:

10606

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00187

AC:

127

AN:

68030

Other (OTH)

AF:

0.00142

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00183

Hom.:

Bravo

AF:

0.00174

TwinsUK

AF:

0.00162

AC:

ALSPAC

AF:

0.00182

AC:

ESP6500AA

AF:

0.000454

AC:

ESP6500EA

AF:

0.00291

AC:

ExAC

AF:

0.00113

AC:

137

EpiCase

AF:

0.00218

EpiControl

AF:

0.00202

ClinVar

ClinVar submissions

Significance:Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.18

BayesDel_addAF

Benign

-0.55

BayesDel_noAF

Benign

-0.57

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Uncertain

0.53

Eigen

Benign

-0.54

Eigen_PC

Benign

-0.57

FATHMM_MKL

Benign

0.062

LIST_S2

Benign

0.63

M_CAP

Benign

0.0080

MetaRNN

Benign

0.0074

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.2

PhyloP100

0.044

PrimateAI

Benign

0.48

PROVEAN

Uncertain

-4.1

REVEL

Benign

0.025

Sift

Benign

0.057

Sift4G

Benign

0.073

Polyphen

0.13

Vest4

0.085

MVP

0.25

MPC

0.47

ClinPred

0.017

GERP RS

2.6

Varity_R

0.31

gMVP

0.30

Mutation Taster

=96/4

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over