NM_000760.4:c.922C>T

Variant names:

• chr1-36472313-G-A
• rs606231473
• NM_000760.4:c.922C>T

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PM2 PP3_Moderate PP5_Very_Strong

The NM_000760.4(CSF3R):​c.922C>T​(p.Arg308Cys) variant causes a missense change. The variant allele was found at a frequency of 0.00000274 in 1,461,872 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R308H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: CSF3R NM_000760.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 4.31
• Publications: 7 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: Labcorp Genetics (formerly Invitae), Ambry Genetics, Orphanet

ENSG00000297367 (HGNC:):

ACMG classification

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, 0.916
• PP5: Variant 1-36472313-G-A is Pathogenic according to our data. Variant chr1-36472313-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 161982.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CSF3R	NM_000760.4	c.922C>T	p.Arg308Cys	missense_variant	Exon 8 of 17	ENST00000373106.6	NP_000751.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CSF3R	ENST00000373106.6	c.922C>T	p.Arg308Cys	missense_variant	Exon 8 of 17	1	NM_000760.4	ENSP00000362198.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461872 Hom.: 0 Cov.: 32 AF XY: 0.00000275 AC XY: 2 AN XY: 727242

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53412

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1112000

Other (OTH) AF: 0.0000166 AC: 1 AN: 60396

GnomAD4 genome Cov.: 32

Alfa AF: 0.00000548 Hom.: 0

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Autosomal recessive severe congenital neutropenia due to CSF3R deficiency Pathogenic:2

Jun 12, 2014

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Oct 15, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 308 of the CSF3R protein (p.Arg308Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with autosomal recessive severe congenital neutropenia (PMID: 24753537, 31321910). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 161982). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt CSF3R protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects CSF3R function (PMID: 24753537, 28652245). 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. -

Severe congenital neutropenia Pathogenic:1

Jun 01, 2013

Klein lab, Ludwig-Maximilians-University

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: in vitro

Neutropenia that is unresponsive to recombinant human G-CSF treatment -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.49
BayesDel_addAF	Pathogenic	0.29	D
BayesDel_noAF	Pathogenic	0.18
CADD	Pathogenic	29
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.64	D;.;.;D;.
Eigen	Pathogenic	0.69
Eigen_PC	Uncertain	0.61
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Uncertain	0.93	.;.;D;D;D
M_CAP	Pathogenic	0.48	D
MetaRNN	Pathogenic	0.92	D;D;D;D;D
MetaSVM	Uncertain	-0.19	T
MutationAssessor	Pathogenic	3.4	M;M;M;M;M
PhyloP100		4.3
PrimateAI	Uncertain	0.60	T
PROVEAN	Pathogenic	-5.5	D;D;D;D;D
REVEL	Pathogenic	0.81
Sift	Pathogenic	0.0	D;D;D;D;D
Sift4G	Pathogenic	0.0010	D;D;D;D;D
Polyphen		1.0	D;D;D;D;D
Vest4		0.97
MutPred		0.63		Loss of MoRF binding (P = 0.0528);Loss of MoRF binding (P = 0.0528);Loss of MoRF binding (P = 0.0528);Loss of MoRF binding (P = 0.0528);Loss of MoRF binding (P = 0.0528);
MVP		0.94
MPC		1.2
ClinPred		0.99	D
GERP RS		3.9
Varity_R		0.73
gMVP		0.91
Mutation Taster		=1/99	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: rs606231473; hg19: chr1-36937914; COSMIC: COSV58969464;