NM_000760.4:c.2422G>A

Variant names:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

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. 12/20 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

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 1.42

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -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 [Likely_benign]. Clinvar id is 434833.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-36466446-C-T is described in Lovd as [Likely_benign].

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 male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CSF3R	NM_000760.4 link	c.2422G>A	p.Glu808Lys	missense_variant	Exon 17 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.2422G>A	p.Glu808Lys	missense_variant	Exon 17 of 17	1	NM_000760.4	ENSP00000362198.2		Q99062-1

Frequencies

GnomAD3 genomes

AF:

0.00572

AC:

870

AN:

152222

Hom.:

Cov.:

show subpopulations

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

GnomAD3 exomes

AF:

0.00653

AC:

1618

AN:

247678

Hom.:

AF XY:

0.00646

AC XY:

868

AN XY:

134298

show subpopulations

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 SAS exome

AF:

0.00174

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.:

Cov.:

AF XY:

0.00732

AC XY:

5319

AN XY:

726710

show subpopulations

Gnomad4 AFR exome

AF:

0.00161

Gnomad4 AMR exome

AF:

0.00828

Gnomad4 ASJ exome

AF:

0.0165

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00207

Gnomad4 FIN exome

AF:

0.00180

Gnomad4 NFE exome

AF:

0.00836

Gnomad4 OTH exome

AF:

0.00753

GnomAD4 genome

AF:

0.00571

AC:

870

AN:

152340

Hom.:

Cov.:

AF XY:

0.00541

AC XY:

403

AN XY:

74490

show subpopulations

Gnomad4 AFR

AF:

0.00188

Gnomad4 AMR

AF:

0.00745

Gnomad4 ASJ

AF:

0.0150

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000829

Gnomad4 FIN

AF:

0.00169

Gnomad4 NFE

AF:

0.00845

Gnomad4 OTH

AF:

0.0113

Alfa

AF:

0.00809

Hom.:

Bravo

AF:

0.00620

TwinsUK

AF:

0.00809

AC:

ALSPAC

AF:

0.00882

AC:

ESP6500AA

AF:

0.00227

AC:

ESP6500EA

AF:

0.00826

AC:

ExAC

AF:

0.00577

AC:

700

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Oct 14, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

CSF3R: BP4, BS1, BS2 -

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

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 v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.38

BayesDel_noAF

Benign

-0.31

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.11

T;.;T

Eigen

Benign

0.051

Eigen_PC

Benign

0.027

FATHMM_MKL

Benign

0.14

LIST_S2

Benign

0.77

.;T;T

MetaRNN

Benign

0.0042

T;T;T

MetaSVM

Benign

-0.82

MutationAssessor

Uncertain

2.7

M;.;M

PrimateAI

Benign

0.41

PROVEAN

Benign

-1.1

N;N;N

REVEL

Benign

0.086

Sift

Benign

0.057

T;D;T

Sift4G

Uncertain

0.013

D;D;D

Polyphen

0.99

D;D;D

Vest4

0.099

MVP

0.82

MPC

0.96

ClinPred

0.021

GERP RS

3.7

Varity_R

0.20

gMVP

0.43

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over