NM_000760.4:c.2422G>A

Variant names:

• chr1-36466446-C-T
• rs146617729
• NM_000760.4:c.2422G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000760.4(CSF3R):​c.2422G>A​(p.Glu808Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00733 in 1,613,282 control chromosomes in the GnomAD database, including 57 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E808G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0057 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0075 (55 hom.)
• Consequence: CSF3R NM_000760.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 1.42
• Publications: 27 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0042365193).
• BP6: Variant 1-36466446-C-T is Benign according to our data. Variant chr1-36466446-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 434833.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00571 (870/152340) while in subpopulation NFE AF = 0.00845 (575/68022). AF 95% confidence interval is 0.00788. There are 2 homozygotes in GnomAd4. There are 403 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 2 AR,AD gene

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CSF3R	NM_000760.4	MANE Select	c.2422G>A	p.Glu808Lys	missense	Exon 17 of 17	NP_000751.1
	CSF3R	NM_156039.3		c.2503G>A	p.Glu835Lys	missense	Exon 17 of 17	NP_724781.1
	CSF3R	NM_172313.3		c.2247+175G>A		intron	N/A	NP_758519.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CSF3R	ENST00000373106.6	TSL:1 MANE Select	c.2422G>A	p.Glu808Lys	missense	Exon 17 of 17	ENSP00000362198.2
	CSF3R	ENST00000373103.5	TSL:1	c.2503G>A	p.Glu835Lys	missense	Exon 17 of 17	ENSP00000362195.1
	CSF3R	ENST00000373104.5	TSL:1	c.2247+175G>A		intron	N/A	ENSP00000362196.1

Frequencies

GnomAD3 genomes AF: 0.00572 AC: 870 AN: 152222 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.00188

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00746

Gnomad ASJ AF: 0.0150

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000829

Gnomad FIN AF: 0.00169

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.00845

Gnomad OTH AF: 0.0115

GnomAD2 exomes AF: 0.00653 AC: 1618 AN: 247678 AF XY: 0.00646

Gnomad AFR exome AF: 0.00166

Gnomad AMR exome AF: 0.00843

Gnomad ASJ exome AF: 0.0186

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00188

Gnomad NFE exome AF: 0.00852

Gnomad OTH exome AF: 0.0120

GnomAD4 exome AF: 0.00750 AC: 10958 AN: 1460942 Hom.: 55 Cov.: 31 AF XY: 0.00732 AC XY: 5319 AN XY: 726710

African (AFR) AF: 0.00161 AC: 54 AN: 33470

American (AMR) AF: 0.00828 AC: 369 AN: 44568

Ashkenazi Jewish (ASJ) AF: 0.0165 AC: 430 AN: 26090

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39678

South Asian (SAS) AF: 0.00207 AC: 178 AN: 86118

European-Finnish (FIN) AF: 0.00180 AC: 96 AN: 53340

Middle Eastern (MID) AF: 0.0152 AC: 86 AN: 5642

European-Non Finnish (NFE) AF: 0.00836 AC: 9290 AN: 1111710

Other (OTH) AF: 0.00753 AC: 454 AN: 60326

GnomAD4 genome AF: 0.00571 AC: 870 AN: 152340 Hom.: 2 Cov.: 32 AF XY: 0.00541 AC XY: 403 AN XY: 74490

African (AFR) AF: 0.00188 AC: 78 AN: 41588

American (AMR) AF: 0.00745 AC: 114 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.0150 AC: 52 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.000829 AC: 4 AN: 4824

European-Finnish (FIN) AF: 0.00169 AC: 18 AN: 10626

Middle Eastern (MID) AF: 0.0170 AC: 5 AN: 294

European-Non Finnish (NFE) AF: 0.00845 AC: 575 AN: 68022

Other (OTH) AF: 0.0113 AC: 24 AN: 2116

Alfa AF: 0.00793 Hom.: 17

Bravo AF: 0.00620

TwinsUK AF: 0.00809 AC: 30

ALSPAC AF: 0.00882 AC: 34

ESP6500AA AF: 0.00227 AC: 10

ESP6500EA AF: 0.00826 AC: 71

ExAC AF: 0.00577 AC: 700

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Aug 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

CSF3R: BP4, BS2

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Oct 14, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not specified Benign:1

Sep 23, 2016

Genetic Services Laboratory, University of Chicago

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Jan 30, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Hereditary neutrophilia;C4310764:Autosomal recessive severe congenital neutropenia due to CSF3R deficiency Benign:1

Jul 02, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.38	T
BayesDel_noAF	Benign	-0.31
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.11	T
Eigen	Benign	0.051
Eigen_PC	Benign	0.027
FATHMM_MKL	Benign	0.14	N
LIST_S2	Benign	0.77	T
MetaRNN	Benign	0.0042	T
MetaSVM	Benign	-0.82	T
MutationAssessor	Uncertain	2.7	M
PhyloP100		1.4
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.086
Sift	Benign	0.057	T
Sift4G	Uncertain	0.013	D
Polyphen		0.99	D
Vest4		0.099
MVP		0.82
MPC		0.96
ClinPred		0.021	T
GERP RS		3.7
Varity_R		0.20
gMVP		0.43
Mutation Taster		=99/1	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: rs146617729; hg19: chr1-36932047; COSMIC: COSV58963566; COSMIC: COSV58963566;