rs796065343

Positions:

• chr1-36467833-G-A

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM2 PP3_Moderate PP5_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
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 6.02

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]

ACMG classification

Verdict is Pathogenic. Variant got 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 [Likely_pathogenic]. Clinvar id is 208339.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CSF3R	NM_000760.4	c.1853C>T	p.Thr618Ile	missense_variant	14/17	ENST00000373106.6	NP_000751.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CSF3R	ENST00000373106.6	c.1853C>T	p.Thr618Ile	missense_variant	14/17	1	NM_000760.4	ENSP00000362198	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Early T cell progenitor acute lymphoblastic leukemia Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Center for Advanced Molecular Diagnostics, Cytogenetics Laboratory, Brigham and Women's Hospital

-

Activating CSF3R mutation found in ETP-ALL and chronic neutrophilic leukemia -

Chronic myelogenous leukemia, BCR-ABL1 positive Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

Dec 26, 2014

- -

Autosomal recessive severe congenital neutropenia due to CSF3R deficiency Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Mar 15, 2023

In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Experimental studies have shown that this missense change affects CSF3R function (PMID: 24081659, 24403076, 30967555). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt CSF3R protein function. ClinVar contains an entry for this variant (Variation ID: 208339). This variant is a well-known somatic variant that has been reported in the literature in individuals affected with chronic neutrophilic leukemia, atypical chronic myeloid leukemia, and acute lymphoblastic leukemia (PMID: 25491280, 26875968, 28209919, 24614839, 24854193, 28219221, 27148573, 23604229, 28762112, 25932451). Rarely, this variant has also been observed as a germline variant in individuals with chronic neutrophilic leukemia (PMID: 31697825, 27581359). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 618 of the CSF3R protein (p.Thr618Ile). -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Clinical Genetics and Genomics, Karolinska University Hospital

Nov 12, 2015

- -

Acute myeloid leukemia Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

Oct 02, 2014

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.63
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Uncertain	0.040
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.65	D;.;.;D;.
Eigen	Uncertain	0.58
Eigen_PC	Uncertain	0.51
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.78	.;.;T;T;T
M_CAP	Uncertain	0.11	D
MetaRNN	Pathogenic	0.86	D;D;D;D;D
MetaSVM	Uncertain	-0.081	T
MutationAssessor	Uncertain	2.7	M;M;M;M;M
MutationTaster	Benign	0.68	D;D;D;D;D;D;D;D
PrimateAI	Uncertain	0.54	T
PROVEAN	Pathogenic	-4.6	D;D;D;D;D
REVEL	Uncertain	0.41
Sift	Pathogenic	0.0	D;D;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;D;D
Polyphen		1.0	D;D;D;D;D
Vest4		0.87
MutPred		0.65		Loss of glycosylation at T618 (P = 0.0135);Loss of glycosylation at T618 (P = 0.0135);Loss of glycosylation at T618 (P = 0.0135);Loss of glycosylation at T618 (P = 0.0135);Loss of glycosylation at T618 (P = 0.0135);
MVP		0.92
MPC		1.0
ClinPred		1.0	D
GERP RS		4.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.67
gMVP		0.93

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: rs796065343; hg19: chr1-36933434; COSMIC: COSV58963463; COSMIC: COSV58963463;