Genetic Variant NM_000760.4:c.1853C>T (chr1-36467833-G-A) – ACMG Classification: Pathogenic (12 pts)

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PM2PP3_ModeratePP5_Very_Strong

The NM_000760.4(CSF3R):c.1853C>T(p.Thr618Ile) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: not found (cov: 33)

Consequence

CSF3R
NM_000760.4 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3

Conservation

PhyloP100: 6.02

Publications

170 publications found

Variant links:

Genes affected

CSF3R (HGNC:2439): (colony stimulating factor 3 receptor) The protein encoded by this gene is the receptor for colony stimulating factor 3, a cytokine that controls the production, differentiation, and function of granulocytes. The encoded protein, which is a member of the family of cytokine receptors, may also function in some cell surface adhesion or recognition processes. Alternatively spliced transcript variants have been described. Mutations in this gene are a cause of Kostmann syndrome, also known as severe congenital neutropenia. [provided by RefSeq, Aug 2010]

CSF3R Gene-Disease associations (from GenCC):

hereditary neutrophilia
Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet
autosomal recessive severe congenital neutropenia due to CSF3R deficiency
Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Ambry Genetics, Orphanet, Labcorp Genetics (formerly Invitae)

CSF3R links:

ENSG00000297367 (HGNC:):

ENSG00000297367 links:

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ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 12 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.857

PP5

Variant 1-36467833-G-A is Pathogenic according to our data. Variant chr1-36467833-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 208339.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000760.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CSF3R	NM_000760.4	MANE Select	c.1853C>T	p.Thr618Ile	missense	Exon 14 of 17	NP_000751.1	Q99062-1
CSF3R	NM_156039.3		c.1853C>T	p.Thr618Ile	missense	Exon 14 of 17	NP_724781.1	Q99062-3
CSF3R	NM_172313.3		c.1853C>T	p.Thr618Ile	missense	Exon 14 of 18	NP_758519.1	Q99062-4

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CSF3R	ENST00000373106.6	TSL:1 MANE Select	c.1853C>T	p.Thr618Ile	missense	Exon 14 of 17	ENSP00000362198.2	Q99062-1
CSF3R	ENST00000373103.5	TSL:1	c.1853C>T	p.Thr618Ile	missense	Exon 14 of 17	ENSP00000362195.1	Q99062-3
CSF3R	ENST00000373104.5	TSL:1	c.1853C>T	p.Thr618Ile	missense	Exon 14 of 18	ENSP00000362196.1	Q99062-4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

ClinVar submissions

Significance:Pathogenic/Likely pathogenic

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Autosomal recessive severe congenital neutropenia due to CSF3R deficiency (1)

Early T cell progenitor acute lymphoblastic leukemia (1)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.63

BayesDel_addAF

Pathogenic

0.19

BayesDel_noAF

Uncertain

0.040

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.65

Eigen

Uncertain

0.58

Eigen_PC

Uncertain

0.51

FATHMM_MKL

Uncertain

0.96

LIST_S2

Benign

0.78

M_CAP

Uncertain

0.11

MetaRNN

Pathogenic

0.86

MetaSVM

Uncertain

-0.081

MutationAssessor

Uncertain

2.7

PhyloP100

6.0

PrimateAI

Uncertain

0.54

PROVEAN

Pathogenic

-4.6

REVEL

Uncertain

0.41

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.87

MutPred

0.65

Loss of glycosylation at T618 (P = 0.0135)

MVP

0.92

MPC

1.0

ClinPred

1.0

GERP RS

4.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.67

gMVP

0.93

Mutation Taster

=0/100

disease causing (ClinVar)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over