1-36471505-C-T

Variant names:

• chr1-36471505-C-T
• rs3918019
• NM_000760.4:c.1213G>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.1213G>A​(p.Glu405Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00441 in 1,614,232 control chromosomes in the GnomAD database, including 25 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0047 (9 hom., cov: 33)
  • Exomes 𝑓: 0.0044 (16 hom.)
• Consequence: CSF3R NM_000760.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 1.44
• Publications: 11 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=0.006228626).
• BP6: Variant 1-36471505-C-T is Benign according to our data. Variant chr1-36471505-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 476293.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 = 0.00467 (711/152340) while in subpopulation NFE AF = 0.00526 (358/68034). AF 95% confidence interval is 0.00481. There are 9 homozygotes in GnomAd4. There are 441 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 9 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.1213G>A	p.Glu405Lys	missense	Exon 10 of 17	NP_000751.1
	CSF3R	NM_156039.3		c.1213G>A	p.Glu405Lys	missense	Exon 10 of 17	NP_724781.1
	CSF3R	NM_172313.3		c.1213G>A	p.Glu405Lys	missense	Exon 10 of 18	NP_758519.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CSF3R	ENST00000373106.6	TSL:1 MANE Select	c.1213G>A	p.Glu405Lys	missense	Exon 10 of 17	ENSP00000362198.2
	CSF3R	ENST00000373103.5	TSL:1	c.1213G>A	p.Glu405Lys	missense	Exon 10 of 17	ENSP00000362195.1
	CSF3R	ENST00000373104.5	TSL:1	c.1213G>A	p.Glu405Lys	missense	Exon 10 of 18	ENSP00000362196.1

Frequencies

GnomAD3 genomes AF: 0.00467 AC: 711 AN: 152222 Hom.: 9 Cov.: 33

Gnomad AFR AF: 0.000844

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00111

Gnomad ASJ AF: 0.00173

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.0271

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00526

Gnomad OTH AF: 0.00287

GnomAD2 exomes AF: 0.00532 AC: 1338 AN: 251484 AF XY: 0.00553

Gnomad AFR exome AF: 0.000431

Gnomad AMR exome AF: 0.000694

Gnomad ASJ exome AF: 0.00188

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0257

Gnomad NFE exome AF: 0.00619

Gnomad OTH exome AF: 0.00375

GnomAD4 exome AF: 0.00438 AC: 6409 AN: 1461892 Hom.: 16 Cov.: 34 AF XY: 0.00427 AC XY: 3104 AN XY: 727246

African (AFR) AF: 0.000568 AC: 19 AN: 33480

American (AMR) AF: 0.000693 AC: 31 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00149 AC: 39 AN: 26136

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

South Asian (SAS) AF: 0.000174 AC: 15 AN: 86258

European-Finnish (FIN) AF: 0.0233 AC: 1245 AN: 53420

Middle Eastern (MID) AF: 0.000520 AC: 3 AN: 5768

European-Non Finnish (NFE) AF: 0.00437 AC: 4856 AN: 1112010

Other (OTH) AF: 0.00333 AC: 201 AN: 60396

GnomAD4 genome AF: 0.00467 AC: 711 AN: 152340 Hom.: 9 Cov.: 33 AF XY: 0.00592 AC XY: 441 AN XY: 74492

African (AFR) AF: 0.000842 AC: 35 AN: 41584

American (AMR) AF: 0.00111 AC: 17 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00173 AC: 6 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4828

European-Finnish (FIN) AF: 0.0271 AC: 288 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00526 AC: 358 AN: 68034

Other (OTH) AF: 0.00284 AC: 6 AN: 2114

Alfa AF: 0.00417 Hom.: 6

Bravo AF: 0.00247

TwinsUK AF: 0.00512 AC: 19

ALSPAC AF: 0.00545 AC: 21

ESP6500AA AF: 0.000681 AC: 3

ESP6500EA AF: 0.00430 AC: 37

ExAC AF: 0.00514 AC: 624

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00447

EpiControl AF: 0.00492

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Jun 12, 2018

Genetic Services Laboratory, University of Chicago

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not provided Benign:1

Jul 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

CSF3R: BP4, BS2

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.55	T
BayesDel_noAF	Benign	-0.56
CADD	Benign	19
DANN	Uncertain	1.0
DEOGEN2	Benign	0.099	T
Eigen	Benign	-0.62
Eigen_PC	Benign	-0.55
FATHMM_MKL	Benign	0.093	N
LIST_S2	Uncertain	0.88	D
MetaRNN	Benign	0.0062	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.8	L
PhyloP100		1.4
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-0.79	N
REVEL	Benign	0.037
Sift	Benign	0.42	T
Sift4G	Uncertain	0.059	T
Polyphen		0.65	P
Vest4		0.20
MVP		0.43
MPC		0.37
ClinPred		0.0074	T
GERP RS		3.3
PromoterAI		0.0050	Neutral
Varity_R		0.055
gMVP		0.39
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs3918019; hg19: chr1-36937106; COSMIC: COSV105898437; COSMIC: COSV105898437;