rs1332794856

Variant names:

• chr1-36466391-C-T
• rs1332794856
• NM_000760.4:c.2477G>A

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_000760.4(CSF3R):​c.2477G>A​(p.Arg826Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000548 in 1,461,106 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R826W) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000055 (0 hom.)
• Consequence: CSF3R NM_000760.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1 O:1
• Conservation: PhyloP100: -1.31
• Publications: 0 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: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.052992612).

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.2477G>A	p.Arg826Gln	missense	Exon 17 of 17	NP_000751.1	Q99062-1
	CSF3R	NM_156039.3		c.2558G>A	p.Arg853Gln	missense	Exon 17 of 17	NP_724781.1	Q99062-3
	CSF3R	NM_172313.3		c.2248-191G>A		intron	N/A	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.2477G>A	p.Arg826Gln	missense	Exon 17 of 17	ENSP00000362198.2	Q99062-1
	CSF3R	ENST00000373103.5	TSL:1	c.2558G>A	p.Arg853Gln	missense	Exon 17 of 17	ENSP00000362195.1	Q99062-3
	CSF3R	ENST00000373104.5	TSL:1	c.2248-191G>A		intron	N/A	ENSP00000362196.1	Q99062-4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000120 AC: 3 AN: 250388 AF XY: 0.0000148

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000579

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000548 AC: 8 AN: 1461106 Hom.: 0 Cov.: 31 AF XY: 0.00000688 AC XY: 5 AN XY: 726854

African (AFR) AF: 0.00 AC: 0 AN: 33460

American (AMR) AF: 0.0000671 AC: 3 AN: 44702

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26120

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86196

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53408

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5238

European-Non Finnish (NFE) AF: 0.00000360 AC: 4 AN: 1111972

Other (OTH) AF: 0.00 AC: 0 AN: 60312

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000189

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Autosomal recessive severe congenital neutropenia due to CSF3R deficiency (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.066
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.58
CADD	Benign	1.1
DANN	Benign	0.75
DEOGEN2	Benign	0.069	T
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.0086	N
LIST_S2	Benign	0.72	T
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.053	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.20	N
PhyloP100		-1.3
PrimateAI	Benign	0.18	T
PROVEAN	Benign	0.31	N
REVEL	Benign	0.044
Sift	Benign	0.51	T
Sift4G	Benign	0.64	T
Polyphen		0.23	B
Vest4		0.063
MutPred		0.42		Loss of sheet (P = 7e-04)
MVP		0.29
MPC		0.34
ClinPred		0.037	T
GERP RS		-6.2
Varity_R		0.030
gMVP		0.24
Mutation Taster		=94/6	polymorphism

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: rs1332794856; hg19: chr1-36931992;