NM_000760.4:c.1853C>T

Variant names:

• chr1-36467833-G-A
• rs796065343
• NM_000760.4:c.1853C>T

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PS3 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 (★★). ClinVar reports functional evidence for this variant: "SCV001235833: Experimental studies have shown that this missense change affects CSF3R function (PMID:24081659, 24403076, 30967555).".

• Frequency: Genomes: not found (cov: 33)
• Consequence: CSF3R NM_000760.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3 O:1
• Conservation: PhyloP100: 6.02
• Publications: 172 publications found

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)

ENSG00000297367 (HGNC:):

ACMG classification

Our verdict: Pathogenic. The variant received 16 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV001235833: Experimental studies have shown that this missense change affects CSF3R function (PMID: 24081659, 24403076, 30967555).
• 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

Sel.	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

Sel.	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.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
1	-	-	Autosomal recessive severe congenital neutropenia due to CSF3R deficiency (1)
1	-	-	Early T cell progenitor acute lymphoblastic leukemia (1)
1	-	-	not provided (1)
-	-	-	Neoplasm (1)

Computational scores

Source: dbNSFP v4.9

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
Eigen	Uncertain	0.58
Eigen_PC	Uncertain	0.51
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.78	T
M_CAP	Uncertain	0.11	D
MetaRNN	Pathogenic	0.86	D
MetaSVM	Uncertain	-0.081	T
MutationAssessor	Uncertain	2.7	M
PhyloP100		6.0
PrimateAI	Uncertain	0.54	T
PROVEAN	Pathogenic	-4.6	D
REVEL	Uncertain	0.41
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.87
MutPred		0.65		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
Mutation Taster		=0/100	disease causing (ClinVar)

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