1-36469807-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_000760.4(CSF3R):c.1319G>A(p.Arg440Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0047 in 1,614,090 control chromosomes in the GnomAD database, including 29 homozygotes. 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 Likely benign (★★).

Frequency

Genomes: 𝑓 0.0041 ( 5 hom., cov: 33)

Exomes 𝑓: 0.0048 ( 24 hom. )

Consequence

CSF3R
NM_000760.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: -1.36

Publications

13 publications found

Variant links:

COSMIC-nc: COSV105898479

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

CSF3R links:

ENSG00000297367 (HGNC:):

ENSG00000297367 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0032138526).

BP6

Variant 1-36469807-C-T is Benign according to our data. Variant chr1-36469807-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 210791.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00413 (629/152306) while in subpopulation AMR AF = 0.00882 (135/15302). AF 95% confidence interval is 0.00761. There are 5 homozygotes in GnomAd4. There are 301 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 5 AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CSF3R	NM_000760.4 link	c.1319G>A	p.Arg440Gln	missense_variant	Exon 11 of 17	ENST00000373106.6	NP_000751.1	Q99062-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CSF3R	ENST00000373106.6 link	c.1319G>A	p.Arg440Gln	missense_variant	Exon 11 of 17	1	NM_000760.4	ENSP00000362198.2		Q99062-1

Frequencies

GnomAD3 genomes

AF:

0.00413

AC:

629

AN:

152188

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000772

Gnomad AMI

AF:

0.0440

Gnomad AMR

AF:

0.00883

Gnomad ASJ

AF:

0.000865

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00283

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00557

Gnomad OTH

AF:

0.00430

GnomAD2 exomes

AF:

0.00329

AC:

822

AN:

250068

AF XY:

0.00320

show subpopulations

Gnomad AFR exome

AF:

0.000573

Gnomad AMR exome

AF:

0.00468

Gnomad ASJ exome

AF:

0.000498

Gnomad EAS exome

AF:

0.0000544

Gnomad FIN exome

AF:

0.00256

Gnomad NFE exome

AF:

0.00495

Gnomad OTH exome

AF:

0.00475

GnomAD4 exome

AF:

0.00476

AC:

6960

AN:

1461784

Hom.:

Cov.:

AF XY:

0.00457

AC XY:

3323

AN XY:

727194

show subpopulations

African (AFR)

AF:

0.00105

AC:

AN:

33480

American (AMR)

AF:

0.00501

AC:

224

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.000612

AC:

AN:

26136

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39700

South Asian (SAS)

AF:

0.0000232

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00287

AC:

153

AN:

53318

Middle Eastern (MID)

AF:

0.000693

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00563

AC:

6262

AN:

1112006

Other (OTH)

AF:

0.00435

AC:

263

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.480

Heterozygous variant carriers

406

812

1218

1624

2030

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

250

500

750

1000

1250

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00413

AC:

629

AN:

152306

Hom.:

Cov.:

AF XY:

0.00404

AC XY:

301

AN XY:

74478

show subpopulations

African (AFR)

AF:

0.000770

AC:

AN:

41570

American (AMR)

AF:

0.00882

AC:

135

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.000865

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5176

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00283

AC:

AN:

10618

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00557

AC:

379

AN:

68022

Other (OTH)

AF:

0.00425

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

119

149

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00449

Hom.:

Bravo

AF:

0.00433

TwinsUK

AF:

0.00405

AC:

ALSPAC

AF:

0.00675

AC:

ESP6500AA

AF:

0.000908

AC:

ESP6500EA

AF:

0.00477

AC:

ExAC

AF:

0.00297

AC:

361

Asia WGS

AF:

0.00144

AC:

AN:

3478

EpiCase

AF:

0.00567

EpiControl

AF:

0.00628

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not specified

Benign:1

Jun 20, 2021

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

Jan 30, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.065

BayesDel_addAF

Benign

-0.57

BayesDel_noAF

Benign

-0.59

CADD

Benign

3.5

(source)

DANN

Benign

0.62

DEOGEN2

Benign

0.065

T;.;.;T;.

Eigen

Benign

-2.0

Eigen_PC

Benign

-2.0

FATHMM_MKL

Benign

0.011

LIST_S2

Benign

0.68

.;.;T;T;T

M_CAP

Benign

0.015

MetaRNN

Benign

0.0032

T;T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.3

L;L;L;L;L

PhyloP100

-1.4

PrimateAI

Benign

0.21

PROVEAN

Benign

-0.020

N;N;N;N;N

REVEL

Benign

0.017

Sift

Benign

0.44

T;T;T;T;T

Sift4G

Benign

0.43

T;T;T;T;T

Polyphen

0.026

B;B;B;B;B

Vest4

0.055

MVP

0.38

MPC

0.34

ClinPred

0.0060

GERP RS

-11

Varity_R

0.033

gMVP

0.33

Mutation Taster

=100/0

polymorphism

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over